The ASTRA study (Antiretrovirals, Sexual Transmission Risk and Attitudes) is a UK multicentre prospective study using self-completed questionnaires relating to HIV and depression in over 3000 HIV positive people. Importantly, the study also correlates responses to adherence and clinical outcomes.

The PHQ-9 questionnaire used in the study classifies participants according to presence/absence of depressive disorder (DD) or major depressive disorder (MDD) and a depression severity score (DSS) that divided diagnoses (from a scale of 0-27) into none, minimal, mild, moderate or severe.

Results from the first 2175 reponses (from February to November 2010) were presented by Fiona Lampe from University College London in an oral abstract session. Baseline demographics for this analysis included: 16% women; 73% MSM; 10% heterosexual men. Mean age was 44 (range 18-80). Ethnic classification was: 70% white; 15% Black African; 14% other ethnicity. Approximately 86% were on ART, 9% of whom were not suppressed (VL >50 copies/mL.

For the primary endpoints, the prevalence was 26.6% (95%C! 24.8-28.5) for DD and 19.1% (95% CI 17.4-20.7%) for MDD, with 27% participants having moderate or severe depression by DSS (>/=10/27).

Perhaps surprisingly, in multivariate analysis, there were no significant differences in DD by gender, ethnicity, country of birth or ART. Younger age was associated with higher depression rates (32% age <30 to 17% at age >60, p=0.028

Significant associations (p<0.001 for each trend) were seen with socio-economic factors including employment status (15% employed, 43% unemployed, 52% sick/disabled), education level (19% university vs 32% other), income (defined as ‘money to cover basis needs: 13% ‘yes mostly’ through to 53% ‘no’) and social support – a measure of supporting relationships (9% “high” through to 66% “low”).

Depression also correlated positively with duration of infection (20% <2 years, 24% 2-10 years, 30% 10-20 years and 35% >30 years), which is interesting given that depression was higher with younger age. Current CD4 count or ART status had no relationship to depression scores.

Higher rates of depression were closely related to lower adherence and lower rates of viral suppression. This ranged from 24% in people who had not missed ART in the past two weeks to 29% with one missed dose, 34% with two missed doses and 42% with 3 or more missed doses.

The percentage of patients with detectable viral load by depression index 14% for those with DD vs 7% for those with no DD, 13% vs 8% for MDD versus no MDD, and ranged from 7% none to 18% severe (DSS) in the non-depressed vs severely depressed groups respectively. The association between depression and viraemia remained significant after adjusting for clinic and self-reported adherence.

The study also indicated that these symptoms may be largely undiagnosed and untreated for many patients. Of the 579 people with depressive disorder (DD) by questionnaire 241 were receiving medication or other treatment and 338 were not. Conversely, of the 1596 people without depression, 200 were on (presumably effective) treatment and 1396 were not.

The total prevalence of depression (symptoms or treatment) was 35.8% (779/2175) in this study, of whom 43% (338/779) were untreated.

COMMENT

This is a large study that included six different UK centres (Royal Free, Mortimer Market, Homerton, North Manchester, Brighton and Eastbourne) with a broad patient demographic.

It is probably the largest UK study to date to comprehensively look at HIV and depressive symptoms and highlights very high rates of depression with a strong indication that this is likely to be under diagnosed and under treated.

These results, especially if confirmed in the full analysis (enrollment is now completed) support the important of indentification and management of depression as an important part of HIV care.

Reference

Lampe F et al. Depression and virological status among UK HIV outpatients: results from a multicentre study. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O10.

Further details, including the slides from this presentation are on the ASTRA study website:

http://www.astra-study.org/

High levels of treatment response to chemotherapy for Hodgkins Lymphoma (HL) in the HAART era were reported in a combined analysis from five clinics, showing similar rates of event-free and overall survival compared to HIV negative controls.

Chloe Orkin and colleagues analysed all cases of HL diagnosed at five London teaching hospitals from 1997-2010 who were treated with 4-6 cycles of AVBD (adriamycin, bleomycin, viznblastine and dacarbazine). Of these, 97/237 were HIV positive and 90/97 were on HAART during HL treatment. HIV viral load was undetectable in 52/86 HIV positive patients with data and low (<6,000 c/mL) in others but 53% (47/97) had CD4 <200 cells/mm3.

HIV patients were older (median age: 41 vs 31 years, p<0.001), more likely to be male (88% vs 59%, p<0.001). They also had higher rates of mixed cellularity (54% vs 19%, p<0.001) and had more advanced disease. This included 80% vs 33% with stage 3/4 at diagnosis (p<0.001), 81% vs 36% with B-symptoms (p<0.001), 46% vs 20% with Hb level <10.5 g/dL (p<0.001) and 76% vs 35% with albumin <4 g/dL (p<0.001) and a higher International Prognostic Score (IPS 3 in 71% vs 22%, p<0.001).

Over median follow-up of 59 months (range 8–172), similar response rates (74% vs 81%), duration of response (33 vs 44 months), 5-year event-free survival (59% vs 65%) and 5-year overall survival (79% vs 88%) were seen in the HIV positive vs HIV negative groups respectively, see Table 1. In the combined group, 40 patients relapsed at a median time of 7 months (range: 1–106).

Table 1: Responses to ABVD chemotherapy in HIV positive vs HIV negative people

COMMENT

These results are important and impressive, despite including data from the early HAART era, and especially given the more advanced disease at HL diagnosis.

Reference

Orkin C et al. HIV Status does not Impact on Outcome in Patients with Hodgkin Lymphoma Treated with ABVD Chemotherapy in the HAART Era. 18th BHIVA Conference, 18-20 April 2012. Oral abstract O13.

The incidence of anal cancer is higher in HIV positive compared to negative populations with lower rates of clearance (87% vs 38% at 5 years) and progression rates from high-grade anal intraepithelial neoplasia (AIN 2/3) in observational studies range from approximately 8-14% over 5 years.

Thornhill and colleagues reported on retrospective results (median 69 months follow-up, range 36-180 months) from treating 91 patients (35 AIN 3; 56 AIN 2) with laser ablative treatment at Homerton Hospital in east London. [1]

Most patients were male (82/91) and MSM (80/82). Mean age was 36.9 (range 20–68). Of the 56 HIV positive patients, 66% (n=37) had a CD4 nadir of <200 cell/mm3. 45% (25/56) had been HIV positive for 15 years or more.

None of the patients in this cohort developed anal cancer suggesting that treatment may have prevented lesion progression in some patients.

The single case of anal cancer in this cohort, not included in this analysis follow-up was less than 3 years was a 49 year-old man (HIV positive for 21 years) with a CD4 nadir of 8. He had advanced 3 quadrant AIN 3 disease that presented late.

A second poster reported prospective first year results from a new ano-rectal outpatient clinic for HIV positive patients at the Royal Free Hospital. [2]

This is a monthly clinic for patients with a history of anal warts or previously diagnosed AIN. Symptomatic patients are screened by anoscopy +/- (surgical) evaluation under anaesthesia (EUA) where indicated. Patients were referred by their clinic doctor or self referred through promotion throughout the clinic.

Data was compiled from 73 patients seen over 12 months. Median (IQR) demographics included: age 45 years (IQR 41–50) years, 91% were MSM (67/73), 85% Caucasian (61/73). 95% (69/73) were on ART, 82% (60/73) with undetectable viral load. CD4 at presentation and CD4 nadir were 511 (362–741) and 152 (26–288) cells/mm3 respectively. Median time since HIV diagnosis was 15 years (10–20), with 11(6–13) years on HARRT. 75% (55/73) were smokers.

Anoscopy +/- EUA for screening was undertaken for 40% (30/73). Of these 27% (8/30) were diagnosed with AIN: AIN-1 (3), AIN-2 (2), and AIN-3 (3). 3/8 had prior diagnosis of AIN, the remainder were all newly diagnosed. 3/30 (10%) were diagnosed with ASCC and were managed by the surgeons and oncologists.

The clinic plans to expand the service to include a screening clinic specifically targeting all HIV positive, MSM who are >40 years, or have low CD4 nadir, or HIV infection > 10 years to undergo routine screening for AIN with Human Papilloma Virus (HPV) cytology, HPV typing and baseline anoscopy.

COMMENT

Greater awareness of AIN in HIV positive gay men, easier access to screening and the necessary support to diagnose complications is important.

The variable progression rates, lack of natural history data and recent availablility of effective treatments all highlight the urgent need for randomised data for the benefit of screening.

References

1. Thornhill J et al. Treatment of anal intraepithelial neoplasia and prevention of anal carcinoma. 18th BHIVA Conference, 18-20 April 2012. Poster abstract 64.
2. Grover D et al. Anal intraepithelial neoplasia: single centre experience. 18th BHIVA Conference, 18-20 April 2012. Poster abstract 68.

An overview of Kaposi’s Sarcoma (KS) in the HAART era was given by Mark Bower from the Chelsea and Westminster Hospital who focussed on the continued use for KS chemotherapy and included recent cases of KS in patients with high CD4 counts (>350 cells/mm3) and who have undetectable viral load.

While the incidence of KS has dramtically reduced since 1997 and 80% of patients diagnosed with early stage KS (T0) and with good immunity (CD4>150) commonly don’t need additional treatment to ART [2] more advanced staging (T1 – any tumour-associated oedema or ulceration, extensive oral KS or non-nodal visceral KS) and reduced immune function (CD4 <150) should be treatment with liposomal anthracycline in addition to ART (or paclitaxel for refractory KS).

The Chelsea and Westminster Hospital cohort from 1996 to 2012 now includes 521 first cases of KS. Most are men (94%) with 17% (86/521) in black Africans. Median age and CD4 counts at presentation are 38 years (range 16-71) and 168 cells/mm3 (range 0-1200) with 66% (n=342) at stage T0 and 34% (n=177). Survival rates in the T0 and T1 groups at 14 years (Kaplan-Meier) are approximately 80% and 65%, respectively. These differences were driven mainly by an early impact <3 years of visceral involvement and presence of oedema/ulceration (later impact > 6 years), rather than oral involvement.

Of note, 15% of new diagnoses (80/521) were in people on established ART (> 3 months), 6% (n=32) had an undetectable viral load and 4% (n=20) had both undetectable viral load and a CD4 count >350 cells/mm3.

The Chelsea and Westminster group has also reported KS as an IRIS-related complication (defined as rapid KS progression during the 2-4 month window after starting ART) in 7% of patients (10/150) who started ART with a KS diagnosis, but higher rates have been reported (20%) in cohorts that only use ART and not concomitant KS treatment. Recurrent KS has also been reported in virologically suppressed patients with similarly good immune responses.

As well as efficacy in addition to ART reported in a recent randomised clinical study (though not greater survival in an African setting) [4], the importance of KS chemotherapy is also supported by mimimal toxicity or prolonged negative impact on CD4 responses. This is now primarily for any patient with stage T1 disease and for the management of KS related to IRIS or in suppressed patients.

References

1. Bower M. Kaposi’s Sarcoma in the era of HAART. BHIVA invited lecture. 18th BHIVA Conference, 18-20 April 2012.
2. AIDS 2009, 23:1701–6.
3. Bower M et al. Immune Reconstitution Inflammatory Syndrome associated with Kaposi’s Sarcoma. J Clin Oncol 23:5224-5228 (2005). http://jco.ascopubs.org/content/23/22/5224.full.pdf
4. Mosam A et al. A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. JAIDS 2012 (19 March) epub. http://www.ncbi.nlm.nih.gov/pubmed/22395672

Simon Collins, HIV i-Base

An update from the D:A:D cohort on the risk of cardiovascular events was presented as a poster. The D:A:D is a large cohort that includes more than 49,000 HIV positive people from Europe, Australia and the US that in recent years has become sufficiently powered to be able to look at associations between safety outcomes and individual HIV drugs.

The cohort now includes 844 cases of myocardial infarction and 523 strokes, both from over 300,000 patient years of follow up (PYFU) and this year accrued sufficient data on atazanavir (>37,000 PYFU) to present this analysis. Previous associations had been reported for cumulative exposure to indinavir and lopinavir/r but not for saquinavir or fosamprenavir.

The rate of MI was 0.28 /100 PYFY (95%CI 0.26 to 2.30) in those with no exposure to atazanavir and 0.20 (0.12 to 0.32) in those with >3 years exposure. The rate of stroke was 0.17 (0.16 to 0.19) and 0.17 (0.10 to 0.27) in the same groups respectively.

The relative rates (RR) for MI and stroke were 0.95 (95%CI: 0.87, 1.05; p=0.30) and 0.90 (95%CI: 0.81, 1.01; p=0.07) after adjustment for clinical and demographic factors including ARV use. No association was seen with cumulative exposure (<1, 1-2, 2-3, >3 years) or after further adjustment for bilirubin. Rates were similar for atazanavir used with and without ritonavir.

Reference

d’Arminio Monforte A et al. ATV-containing ART is not associated with an increased risk of cardio- or cerebro-vascular events in the D:A:D study. 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle. Poster abstract 823.

http://www.retroconference.org/2012b/Abstracts/45367.htm

Two ongoing concerns for HIV positive people on ART are (1) whether long-term side effects shorten life-expectancy? and (2) is premature ageing related to either ART or HIV?

While both short and medium term outcomes have so far been very good, data for these questions requires following large numbers of patients over many years. Since it is impossible to have randomised control groups, the interpretation of cohort results also needs to consider numerous confounding variables.

The second question is a particular focus for current research. But a new analysis from the EuroSIDA cohort comes close to answering the first. In an article published in the 21 January 2012 edition of AIDS, there was no evidence in this huge cohort that the risk of death, all-cause or AIDS, increased with length of time on ART. [1]

EuroSIDA is one of the largest prospective observational ART cohorts. It includes nearly 17,000 patients from Europe, Israel and Argentina. This cohort’s researchers previously have published important papers showing the benefits of ART on life expectancy. The authors explain that this is the first study “to look into the association of non-AIDS deaths with duration of time spent on combination antiretroviral therapy (cART) and with a long-term perspective of exposure to treatment. The results are reassuring that so far prolonged use of cART does not appear to be leading to increased risk of death due to some previously identified cumulative effect or a drug effect whereby there is a long induction period before disease appears.”

Just over 12,000 patients were followed from baseline, defined as the time of starting ART or enrolment into EuroSIDA after 1996. Three quarters of the cohort is male. About 40% acquired HIV homosexually, 22% from IDU and 30% heterosexually. Interestingly, nearly 60% of the cohort are current or previous smokers and smoking status was unknown in more than 20%. At baseline about 21% were confirmed hepatitis C positive and about 53% were confirmed negative. About 10% had confirmed hypertension and just over 2% confirmed diabetes.

The researchers calculated incidence rates of death, AIDS-related and non-AIDS-related, per 1000 person-years of follow-up stratified by time of exposure to cART (< 2 years, 2 to 3.99 years; 4 to 5.99 years; 6 to 7.99 years and > 8 years).

During 70,613 person years of follow-up, a total of 1,297 patients died. AIDS caused 413 and non-AIDS diseases caused 884 deaths. Incidence rates per 1,000 years of follow-up were 18.3 overall (95% CI: 17.4-19.4), 5.85 for AIDS deaths (95% CI: 5.28-6.41) and 12.5 for non-AIDS deaths (95% CI: 11.7-13.3).

For the non-AIDS related deaths, 121 were due to infections, 182 due to liver-disease, 125 due to cancer, 122 due to cardiovascular disease, 90 due to violence (including suicide) and 91 due to other causes.

The main analysis compared mortality over the predefined periods on ART. The researchers used 2 to 3.99 years on ART as reference. In a multivariate analysis controlling for sex, ethnic origin, region of Europe, hepatitis B and C status, diabetes, hypertension, smoking, viral load, CD4 cell count, prior AIDS and age, they found the following incidence rate ratios of all-cause, AIDS-related and non-AIDS related deaths (see Table 1).

Longer time on ART was associated with a reduction in the risk of liver-related death, violent, and unknown deaths. But longer time on ART was also associated with an increase in mortality attributed to non-AIDS-related cancers. The researchers suggest this “may reflect ageing of the HIV population, as the effect was no longer present after adjustment for time updated age …”

comment

This article is reassuring for people who are recently diagnosed, who have access to modern ARVs and a medical history that is uncomplicated by coinfections or prior drug resistance. It is important that there is no signal of additional risk from treatment that is otherwise stable and effective.

The risk of premature ageing is the focus for research into immune activation and inflammation. It is also dependent on HIV negative controls to understand the impact of residual inflammation in people suppressed on HAART. In an editorial in Current Opinion Infect Diseases, Martin Fisher and Vanessa Cooper suggest caution over links between HIV or ART and ageing. They conclude, “Although undoubtedly there are higher rates of comorbidities in the HIV-positive population [...] Further research is needed to explore the mechanisms by which HIV/HAART may contribute to age-related diseases, the contribution of other important and potentially modifiable risk factors including smoking, alcohol and drug use, and the role of comorbid disease.” [2]

References:

1. Kowalska JD et al. for EuroSIDA. Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. AIDS 26:315-323. (28 January 2012). Free full text online.
   http://journals.lww.com/aidsonline/Fulltext/2012/01280/Long_term_exposure_to_combination_antiretroviral.7.aspx
2. Fisher M and Cooper V. 2012. HIV and ageing: premature ageing or premature conclusions? Curr Opin Infect Dis 25:1-3. Free full text online.
   http://journals.lww.com/co-infectiousdiseases/Fulltext/2012/02000/HIV_and_ageing___premature_ageing_or_premature.2.aspx

Comparing HIV-positive and negative injection drug users (IDUs) in a large Baltimore cohort, researchers determined that HIV infection independently raised the risk of objectively defined frailty and prefrailty. Frailty and prefrailty risks were highest in people with a CD4 count below 350 and a detectable viral load. [1]

Frailty boosts chances of hospital admission, disability, and death in older people without HIV.

In the Multicenter AIDS Cohort Study of HIV-positive and negative gay men. HIV infection raised the odds of earlier frailty [2], and frailty before combination antiretroviral therapy begins independently predicted AIDS or death [3]. But the impact of HIV on frailty risk and clinical outcomes is still in an early phase of study.

In this analysis Johns Hopkins University researchers focused on 1206 current or former IDUs with or without HIV infection seen from 2005 through 2009 in a prospective observational cohort. All cohort members were at least 18 years old and made twice-yearly visits for follow-up. The Hopkins team defined frailty (by the Fried system) as meeting 3 or more of 5 criteria: weakness determined by grip strength, slowed walking speed, weight loss, low physical activity, and exhaustion. They defined prefrailty as one or two of these criteria.

Of the 1206 IDUs assessed, 345 (29%) had HIV infection. Median age stood at 48 years, and one third in both the HIV-positive and negative groups were women. Higher proportions in the HIV group were African American (95.7% versus 87.6%), had less than a high school education (65.2% versus 57.0%), and were hepatitis C positive (93.3% versus 81.0%) (P < 0.05 for all comparisons). Lower proportions of HIV-positive cohort members were recent injectors (36.2% versus 47.4%), actively used alcohol (48.3% versus 56.8%), abused prescription drugs (6.4% versus 12.9%), or had a spouse or common-law partner (4.7% versus 8.8%) (P < 0.05 for all).

HIV-positive people had a median CD4 count of 290, a median CD4 nadir of 138, and a median viral load of 3.1 log (about 1250 copies). Half (51%) were taking combination antiretrovirals, and 21.7% had an AIDS diagnosis.

Overall frailty prevalence stood at 8.3%, with rates of 10.7% in the HIV group and 7.3% in the HIV-negative group; 59% of cohort members met prefrailty criteria. Through 4652 person-visits, both frailty and prefrailty proved more common in older IDUs, women, those with less than a high school education, people without a spouse or partner, those who abused prescription drugs, and those with depressive symptoms. African-American cohort members had a lower risk of prefrailty. Adjusting for all these factors, the researchers determined that HIV infection raised the prefrailty risk 28% (adjusted odds ratio [AOR] 1.28, 95% confidence interval [CI] 1.06 to 1.53), while raising the frailty risk 75% (AOR 1.75, 95% CI 1.27 to 2.39).

Compared with HIV-negative IDUs, HIV-positive cohort members had a higher risk of prefrailty or frailty with worse HIV disease status, as noted by the AORs (and 95% CIs) in Table 1.

The Hopkins teams evaluated frailty as a predictor of new hospital admissions in all 1206 cohort members from July 2005 through December 2009. During that time there were 374 hospital admissions, and the admission rate was significantly greater in frail than in nonfrail people (P = 0.006).

Compared with nonfrail cohort members, prefrail people did not have an independently higher risk of hospital admission, but frail people had a 60% higher risk (adjusted hazard ratio [AHR] 1.59, 95% CI 1.10 to 2.30). Female gender made hospital admission 66% more likely, homelessness raised the odds by 42%, active alcohol use by 32%, hepatitis C by 90%, and prescription drug use by 56%. Compared with HIV-negative people, HIV-positive people with a CD4 count under 350 and a detectable viral load had a doubled risk of hospital admission (AHR 2.12, 95% CI 1.61 to 2.79).

The Johns Hopkins investigators concluded that HIV infection boosts the risk of prefrailty and frailty in current and former IDUs. They proposed that “early identification of frail and prefrail IDUs may provide opportunities for arresting progression to adverse clinical states.”

References:

1. Piggott D et al. Frailty and incident hospitalization in a cohort of HIV-infected and uninfected injection drug users (IDUs). 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract O_06.
2. Desquilbet L et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286.
3. Desquilbet L et al. A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men. J Gerontol A Biol Sci Med Sci. 2011;66:1030-1038.

The executive summary and full guidelines are both available to download in PDF format.

The report is part of the organisations’ HIV and Ageing Consensus Project, developed to assess how the presence of both HIV and common age-associated diseases, alter the optimal treatment of HIV as well as other co-morbidities. The purpose of the report, developed by a panel of experts with experience both in the fields of HIV and Geriatrics, is to provide best practice guidance for HIV practitioners and other health care providers who treat, diagnose and refer older patients with HIV disease.

References:

The HIV and Ageing Consensus Project: Recommended treatment strategies for clinicians managing older patients with HIV.

View the executive summary: (direct PDF download)
http://www.aahivm.org/Upload_Module/upload/HIV%20and%20Aging/AAHIVM%20Executive%20Summary%20FINAL%202.pdf

Full report and guidelines: (direct PDF download)
http://www.aahivm.org/Upload_Module/upload/HIV%20and%20Aging/Aging%20report%20working%20document%20FINAL.pdf

The December 1st issue of Clinical Infectious Diseases contains a raft of papers addressing the issue of HIV and ageing.

A report from the Swiss HIV Cohort Study documents that illnesses typically associated with ageing are now the most common causes of morbidity in their cohort, which contains an increasing proportion of individuals aged 50 or older. [1] In contrast, opportunistic infections make only a minor contribution in the current era of effective antiretroviral therapy (ART). An accompanying editorial by Mike Saag highlights the implications for providing appropriate multidisciplinary care to people with HIV as they age. [2]

While there are ongoing debates about whether HIV infection is linked to premature ageing – some studies have suggested the risk of ageing-associated diseases is increased among HIV-positive people compared to age-matched HIV-negative individuals, while other studies have disputed these findings – the Swiss HIV Cohort Study paper emphasises that whether or not they are occurring sooner, these morbidities are now the main concern in the long-term care of people with HIV. In discussing their findings, the authors note that the incidence of cancer, heart attacks and diabetes among members of their cohort aged 50-64 was higher than described in studies of somewhat comparable HIV-negative cohorts, but they also stress that “a comparison of our results with an age-matched HIV-uninfected population with similar comorbidity or behavior is difficult, because we had no suitable HIV-uninfected control group in our country.”

Giovanni Guaraldi and colleagues from the University of Modena and Reggio Emilia in Italy attempted to address this issue in their study, which compared the occurrence of non-infectious co-morbidities (NICMs) and polypathology (the presence of more than one NICM) among HIV-positive people on ART and a matched HIV-negative control group from the general population (from 2002 through 2009). [3]

The NICMs captured in the study included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. The results revealed that prevalence of NICMs and polypathology was higher in HIV-positive individuals across all age categories. The prevalence of polypathology among people with HIV aged 41-50 was similar to the prevalence among HIV-negative controls aged 51-60.

Interpretation of the findings is complicated by the fact that the data from HIV-positive individuals was all derived from a metabolic clinic at Modena. Part of this population is comprised of local people from main HIV clinic at Modena who are automatically referred to the metabolic clinic if they are on ART. However, the population also includes a large proportion of HIV-positive individuals who are referred to the Modena metabolic clinic from neighboring centers due to metabolic issues such as lipodystrophy, and this would appear to account for the unusually high prevalence of this condition among the study cohort (74%). To assess whether this over-representation of people with metabolic issues had biased their results, the study authors compared the incidence of NICMs and polypathology among the local referrals to those from the neighboring centers but—perhaps surprisingly, as Jacqueline Capeau notes in an accompanying editorial commentary—they found no difference. [4]

The authors conclude: “our findings suggest that an aggressive approach to the screening, diagnosis, and treatment of NICMs is warranted as part of routine healthcare for HIV-infected patients. Furthermore, our data suggest that onset of such screening should commence at a substantially earlier age for HIV-infected persons, compared with HIV-uninfected persons, possibly at least a decade in advance. Additional studies are needed to further evaluate the impact of convergent age-related NICMs on age-related functional status, frailty, and disability among ART-experienced HIV-infected persons and to provide insights into accelerated ageing processes that may be associated with chronic HIV infection.”

Source: TAG Basic Science web log. (1 November 2011).

References

1. Hasse B et al for the Swiss HIV Cohort Study. Morbidity and ageing in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1130
2. Saag MS. Editorial commentary: HIV now firmly established in the Middle Ages. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1140
3. Guaraldi G et al. Premature age-elated comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1120
4. Capeau J. Editorial commentary: Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Hypotheses. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1127

A population-based study carried out in Denmark to assess the risk of cataract surgery among HIV-positive individuals compared to large group of matched HIV-negative controls.

Risk was found to be greater among the HIV-positive population, with the highest risk among those with CD4 T cell counts below 200 (either on or off ART). Individuals on ART with CD4 T cell counts over 200 still showed a higher risk than both the general population and HIV-positive people with over 200 CD4 T cells who had not yet started ART; the authors note this could reflect a contribution of drug side effects or receipt of ART could be acting as a marker for having reached a stage of illness requiring treatment (which in turn is associated with an elevated cataract risk).

Supporting the latter possibility, no association with specific antiretroviral drugs was found. Although the researchers do not claim that their data represents evidence of accelerated ageing in the HIV-positive population, they acknowledge that such a phenomenon “cannot be excluded as a possible part of the explanation.”

Source: TAG Basic Science web log. (1 November 2011).

Reference:

Rasmussen LD et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide population-based cohort study. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
http://cid.oxfordjournals.org/content/53/11/1156

A study published in the July 1st edition of JAIDS by Michelle Yong from The Alfred Hospital, Melbourne, reported a significant association between CD4 count and risk of fractures that was independent of traditional risk factors including corticosteroid use.

The group performed a 1:2 matched case-control study in HIV positive patients attending a single hospital site between 1998 and 2009. Controls were matched on gender, age, and duration of HIV infection.

The overall fracture incidence rate was 0.53 per 100 person-years (95%CI: 0.43 to 0.65) and period prevalence of 3.34 per 100 patients (95% CI: 2.66 to 4.13). There were 73 low trauma fractures in 61 patients. Patients were predominantly male (89%) with a mean age of 49.8 years. Independent risk factors for fragility fracture were a CD4 cell count <200 cells/mm3 (OR 4.91: 95% CI 1.78 to 13.57, p = 0.002), corticosteroids (OR 8.96: 95% CI 1.55 to 51.88, p = 0.014) and anti-epileptic medications (OR: 8.88: 95% CI 1.75 to 44.97, p = 0.008).

No association was found between risk of fracture and HIV viral load (p = 0.18), use of antiretrovirals or class of antiretroviral medication. The majority patients with fracture (88%) had osteopenia or osteoporosis.

Reference:

Yong MK et al. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. JAIDS, 1 July 2011 – Volume 57 – Issue 3 – pp 205-210
http://journals.lww.com/jaids/Fulltext/2011/07010/Low_CD4_Count_Is_Associated_With_an_Increased_Risk.5.aspx

Simon Collins, HIV i-Base

Hearing loss has been associated as a complication in HIV-positive people but it is unclear whether HIV is a direct factor or whether symptoms are more strongly correlated to risk factors reported in the general population. This will be increasingly important as the HIV population ages.

Researchers from Washington DC measured cochlear function in 334 men and 178 women from two of the earliest population cohorts established to look at differences between HIV-positive and HIV-negative patients (MACS and WIHS respectively), and related to this to social factors including noise exposure and HIV and treatment history.

The mean age was 54 years for the men (46% were HIV-positive), and 45 years for the women (77% were HIV-positive). People were excluded if they had hearing-impaired clinical symptoms or recent use of orotoxic medication. Approximately 20% of people in each of the HIV-positive and HIV negative groups self-reported exposure to occupational noise.

Cochlear function was measured by distortion product otoacoustic emission (DPOAE) testing which is a non-invasive procedure using two separate tones to stimulate the cochlea. Each ear was measured twice, with a third test if results were inconsistent and the number of non-responses added as an outcome variable (0-4).

In multivariate analyses, a 10-year increase in age [OR 2.78; 95%CI 2.07, 3.73], being male [OR 5.60; 95%CI 2.98, 10.49], and being non-black [OR 2.75; 95%CI 1.57, 4.83] were significantly associated with a higher number of non-responses (all p<0.001), but not HIV status [OR 1.20; 95%CI 0.7, 2.02; p =0.52 NS]. However, neither occupational or non-occupational noise exposure was associated with reduced function (p=0.33 and p=0.93, respectively).

Age, race, and gender remained significant risk factors for increasing non-responses in the HIV-positive model. However, none of the HIV-related factors including use of monotherapy, combination therapy, HAART use, 100-cell increase in peak CD8, HIV viral load, and 100-cell increase in nadir CD4 count came near approaching statistical significance (with p-values ranging from 0.2 to 0.7).

The researchers concluded that HIV status, combination therapy, nadir CD4 count, peak CD8 count, and HIV viral load did not significantly predict decreased cochlear function in this patient group.

Reference

Torre P et al. Cochlear function among Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS) participants. 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome. Poster abstract TUPE138. Poster. (PDF)

Advances in the treatment of HIV infection with antiretroviral therapy have led to dramatic reductions in opportunistic infections and death.  However, late presentation of HIV remains a problem and is a significant contributory cause to death in HIV-positive persons in the UK.  Furthermore, a recent UK Health Protection Agency (HPA) analysis showed that of 46,700 patients with diagnosed HIV, 19% had CD4 counts <200 cells/mm3 and therefore remain at significant risk of opportunistic infection.

These guidelines have been drawn up to help physicians investigate and manage HIV-positive patients suspected of, or having an opportunistic infection (OI).  The early chapters consider the most common presentations of OI disease such as respiratory, gastrointestinal and neurological disease.  Then follow specific organisms such as Candida spp, herpes simplex virus and varicella zoster virus. Finally, special circumstances including pregnancy, the use of the intensive care unit, fever of undetermined origin and management of imported infections, are also addressed.

Each section contains information on the background, epidemiology, presentation, treatment and prophylaxis of OIs.  Further information on the role of antiretroviral therapy is also discussed (see below).

The Guidelines Writing Group is grateful for all comments, which will be reviewed before publication.

http://www.bhiva.org

In an oral presentation, Andrew Prendergast from Oxford University showed data from a study looking at the impact of cytomegalovirus (CMV) on HIV disease progression in a small group of South African infants. [1]

This was a sub-study of the Paediatric Early HAART STI Study (PEHSS), conducted in Durban. PEHSS was a feasibility trial of three management approaches in HIV-infected infants who were diagnosed by HIV PCR at either one or 28 days old. They were then randomised 2:1 to immediate or deferred antiretroviral therapy (ART). [2]

In this sub-study, the investigators performed real time CMV PCR on cryopreserved plasma samples taken at 3 to 4 months of age. Pre-ART CD4% decline was compared between CMV-positive and CMV-negative infants.

Samples were available for 54/63 (86%) of infants enrolled in PEHSS taken at a median of 98 (IQR 88-103) days; 32/54 (59%) were CMV-positive at time of evaluation. Baseline characteristics, including maternal disease status, were similar between the CMV-positive and negative infants but CMV-positive infants were more likely to be breastfed, p=0.01.

The investigators found no significant clinical differences in the two groups of infants but they noted a trend towards failure to thrive in CMV-positive infants (43% vs 17%, p=0.07).

CD4 percentage at birth was similar between CMV-positive and CMV-negative infants (median 45%, p=0.56). However the decline in CD4 percentage from birth was twice as fast in CMV-positive compared to CMV–negative infants (median 10.5%/month vs 5.0%/month; p=0.007) and pre-ART CD4 percentage nadir was significantly lower (median 21% vs 37%; p<0.0001). CD4% tends to be used as the preferred marker of immune decline in early childhood because it naturally varies less with age than the absolute CD4 count.

They also found after 12 months post-ART initiation that the difference in CD4 percentage persisted in CMV-positive compared to CMV-negative infants (median 29% vs 36%; p=0.004).

Interestingly, however, absolute CD4 count nadir was no different between CMV-positive and CMV-negative infants. Dr Prendergast demonstrated that the CMV-positive infants had a huge CD8 cell expansion associated with CMV infection and this rise in CD8 proportion causes much of the impact on CD4 percentage. These data question the validity of using CD4 percentage as the preferred marker of immunological status in infancy, since the CD8 count has such an impact on the CD4 levels.

As over half of HIV-infected
infants in this study acquired CMV in the first 4 months of life, and these in turn showed more rapid CD4 percentage decline, Dr

Prendergast asked whether CMV prophylaxis or treatment could slow disease progression in infants? Most importantly he emphasised that infants must access early HIV diagnosis and antiretroviral treatment given the speed of CD4 decline, especially in settings of high CMV prevalence.

COMMENT

Although this study is very small it raises questions and adds to the argument for early HIV diagnosis and initiation of treatment in infants.

It would be interesting to look at responses to treatment by CMV status in CHER to see if the CMV effect is supported in larger patient numbers It would also be interesting to look at whether CMV was acquired during pregnancy or at birth, and the risk of transmission through breastfeeding.

Similar findings were recently reported in a western cohort, which supports both early maternal ART in pregnancy and early ART in infected infants. [3]

A number of studies (including one from Jane Deayton at the Royal Free published in the Lancet) have previously reported that CMV viraemia is a risk factor for disease progression, even in the HAART era.

Whilst CMV prophylaxis is not routinely used in adults, pre-emptive therapy is certainly used in transplant recipients, and some groups do believe that CMV prophylaxis should be considered in high-risk groups. So, this is an issue of debate at the moment. Several trials are underway (including one at the RF) of potential CMV vaccines. This may be particularly helpful for pregnant women as CMV during pregnancy is associated with a large proportion of birth abnormalities.

References

Oral abstract presentations are also online as web casts.

1. Prendergast et al. Accelerated HIV disease progression in African infants co-infected with cytomegalovirus. 16th CROI. February 2009. Montreal, Canada Oral abstract 93LB.
http://www.retroconference.org/2009/Abstracts/36757.htm
2. Prendergast et al. Randomised, controlled trial of 3 approaches to management of HIV-infected infants. 15th CROI, February 2008, Boston, USA. Oral abstract 77LB.
http://www.retroconference.org/2008/Abstracts/33523.htm
3. Guibert et al. decreased risk of congenital cytomeglavirus infection in children born to HIV-infected mothers in an era of highly active antiretroviral therapy. CID 48:11 p1516-1526. (1 June 2009).

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.
http://www.hivatis.org

Unfortunately, unlike the main US treatment guidelines, this updated document does not highlight in the text the changes from earlier documents.

However, the introduction states that major changes include:

• Greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists;
• Information regarding the diagnosis and management of immune reconstitution inflammatory syndromes;
• Information regarding the use of interferon-gamma release assays for the diagnosis of latent TB infection;
• Updated information on drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB;
• The addition of a section on hepatitis B virus infection; and
• The addition of malaria to the list of OIs that might be acquired during international travel.

Results of a randomised, double-blind, placebo controlled trial in Tanzania of single high-dose oral fluconazle was reported by Omar Hamza and colleagues from Muhimbili University, Tanzania.

The trial randomised 220 HIV-positive patients with clinical and mycological evidence of oropharyngeal candidiasis to receive oral fluconazole doses of either 750-mg single dose or standard dose of 150 mg once-daily for 2 weeks. Each arm included 110 patients.

Results were similar in each group and are detailed in Table 1. There were no statistically significant differences between the two groups. Approximately 95% patients were clinically cured (OR, 0.825; 95% CI, 0.244–2.789; p=0.99) and 85-75% mycologically cured (OR, 1.780; 95% CI, 0.906–3.496; p=0.129).

Table 1: Results from single dose vs 2-week fluconazole

Overall, clinical cure was not achieved in 11 patients and for all of them, Candida species were isolated from patient specimens at baseline and on day 14. In 33 patients (15.0%), clinical cure was obtained despite persistent positive culture results on day 14 (mycological failure).

No differences were observed in relapse rates (OR, 1.073; 95% CI, 0.456–2.523; P=0.99). The average time to relapse after clinical cure was 18-20 days. Twenty-two (91.7%) of 24 patients who experienced relapse during follow-up had CD4 cell counts <200 cells/mm3, 16 (66.7%) had CD4 cell counts <100 cells/mm3, 17 (70.8%) were not receiving HAART, and 14 (58.3%) had had previous episodes of OPC.

The mean plasma fluconazole concentrations on days 1, 4 or 5, 7, and 14 in the 14-day fluconazole group were 13.35, 5.46, 1.37, and 0.32 mg/L and 4.18, 6.88, 7.94, and 7.62 mg/L, for the single-dose and 14-day groups respectively. These differences were statistically significant for days 1, 7 and 14.

Overall, adverse events were mild, and no differences in frequency of adverse events were noted between patients in the 2 treatment regimens. Because most of the study patients were in an advanced stage of HIV infection and AIDS, abnormalities in full blood count and liver function tests were common.

In this study, the mycological cure rate, with a single-dose treatment of 750 mg fluconazole, was much higher (84.5%) than the 6%–41% mycological cure rates reported from studies using 150mg single dose treatment.

The authors concluded “The use of a single high dose of fluconazole … presents the advantages of simplicity and convenience, thus improving compliance and reducing the cost of therapy. A single dose of five 150-mg tablets is less costly than fourteen 150-mg tablets taken over a 14-day course and, therefore, could be used, especially in resource-limited settings like in sub-Saharan Africa. In addition, administration of the single-dose therapy can be observed directly by medical personnel, thereby assuring patient compliance.”

Ref: Omar J et al. Single-Dose Fluconazole versus Standard 2-Week Therapy for Oropharyngeal Candidiasis in HIV-Infected Patients: A Randomized, Double-Blind, Double-Dummy Trial. Clinical Infectious Diseases 15 November 2008, Vol. 47, No. 10: 1270-1276.

Andrew Zalopa from Stanford University and colleagues presented results from ACTG A5164 Phase 4 study which randomised 282 patients to either immediate or deferred use of ARVs in the context of an acute OI diagnosis for which treatment is available (TB was excluded).

Optimal timing of HAART in this context is currently guided more by expert opinion than data from randomised studies, and is difficult due to the advanced illness of study participants.

Patients needed to be treatment-naive, not to have used ARVs in the previous 8 weeks or not to have used treatment for more than one month if used in the past. Deferred treatment was defined as after OI treatment (at least 4 weeks after randomisation). Randomisation was stratified by OI and CD4 (above and below 50 cells/mm3). Patients with tuberculosis were excluded. The primary week 48 endpoint was an ordered categorical variable of three outcomes: death/AIDS progression; no progression, HIV viral load <50copies/mL; or no progression, viral load <50 copies/mL.

Baseline characteristics included median (IQR) CD4 and viral load counts of 29 (10-55) cells/mm3 and 5.07 (4.71-5.63) log copies/mL. Over 90% were treatment-naive. Median age was 38 years; 85% men/15% women; 37% black, 36% Hispanic, and 23% white.

OIs included PCP (63%), cryptococcal meningitis (13%), pneumonia (10%), other OI including cyrptosporidiosis, toxoplasmosis, CMV and MAC (25%). One third of patients were diagnosed with more than one OI within 30 days.

Immediate and deferred arms started ART with a median (IQR) of 12 (9-13) and 45 (41-55) days, respectively, after treatment for the opportunistic infection had started. 10% of the deferred treatment arm did not start HAART. Choice of ARVs was open with 89% and 85% patients in the immediate and deferred arms respectively, starting with a boosted-PI based regimen.

13% patients were lost to follow-up
(18 in each arm). Although there was no significant difference in the composite primary endpoint with both arms achieved similar CD4 and viral load by week 24, the immediate arm had significant clinical benefits. Immediate HAART led to fewer deaths/AIDS progressions (n=20 vs 34, p =0.035), longer time to death/AIDS progression (stratified HR = 0.53, 99% CI 0.25-1.09, p = 0.02), and shorter time to achieving an increase in CD4 counts to >50 and >100 (median 8.1 vs 3.9 weeks and 11.8 vs 4.2 weeks, both p<0.001), respectively.

There was a trend of earlier ART changes in the immediate arm (p = 0.15), but no significant differences in grade 3 or 4 adverse events, adherence, hospitalizations, or immune reconstitution inflammatory syndrome (8 immediate vs 12 deferred).

The clinical benefits from immediate treatment were driven by the more rapid increase in CD4 count, which decreased the period of vulnerability to new AIDS-related infections and death.

COMMENT

It is important that the question of HAART timing has been answered in a randomised study. The acknowledgement of patients for participating in this study, many of whom were already ‘disenfranchised from the US healthcare system’, was particularly deserved.

Ref: Zolopa A, Andersen J, Komarow L et al. Immediate vs Deferred ART in the Setting of Acute AIDS-related Opportunistic Infection: Final Results of a Randomized Strategy Trial, ACTG A5164. Oral abstract 142.
http://www.retroconference.org/2008/Abstracts/32805.htm

This presentation is also available as a webcast (Wed 6th Feb).

Progressive multifocal leukoencephalopathy (PML) has remained one of the most difficult to manage opportunistic infections and even post HAART is associated with poor prognosis and survival rates.

Several studies at the conference reported on management of PML including an important report from Jacques Gasnault and colleagues from the French ANRS125 study team who presented results from an open-label multicentre pilot study, designed to show whether an intensified ART regimen including T-20 (enfuvirtide) can hasten anti-JCV immune recovery.

The study included 28 HIV-positive patients (22 male) mainly enrolled from April 2005 to September 2006, with a recent clinical history of active PML (within 90 days), PML documented by cerebral imaging, no other likely etiology, polymerase chain reaction (PCR) detection of JCV DNA in cerebrospinal fluid (CSF), or pathological examination.

At baseline, the median CD4 T-cell count was 54 cells/mm3 (range, 2 to 345) and the median plasma HIV load was 4.08 log copies/mL (1.59 to 5.20). JCV DNA was detected in CSF in 78% of cases.

ARV therapy included a 5-drug regimen of tenofovir/FTC/efavirenz/lopinavir/r and T-20 for the 12 naïve patients and 3 or more optimised ARVs plus T-20 for the 16 experienced patients. T-20 was discontinued after the first 6 months in all patients. Follow-up lasted 1 year and the primary endpoint was the survival estimate at month 12.

Five patients died before month 6. On 15 September 2006, the 6-month survival estimate was 0.78 (CI = 0.62 to 0.97). At week 6 and month 6, respectively, 52% and 77% of patients had a plasma HIV load below 40 copies/mL. Median CD4 T-cell counts at week 6 and month 6 were 116 cells/mm3 (8 to 509) and 169 cells/mm3 (28 to 665). At month 6, 10/13 (77%) of patients were negative for JCV DNA detection in CSF and 16/19 (84%) were negative for plasma HIV RNA. The percentages of patients with detectable anti-JCV CD4 T responses (proliferation to purified JCV) and anti-JCV CD8 T-cell responses (interferon-gamma ELISpot with overlapping VP1 peptides) increased between baseline (6% and 29%) and month 6 (62% and 58%).

In an oral overview of PML presented at the conference by David Clifford from Washington University, the proposed mechanism for the ‘outstanding’ survival rates reported in this study was antiviral potency of the regimen, rather than any specific effect of T-20, or even CNS penetration. [2]

This excellent summary also focused on the changing interpretation of MRI scans in diagnosing PML, and questioned whether renaming PML as JCV-related encephalopathy, given the higher proportion of patients now presenting with single focal lesions, and the reduced sensitivity of CNS JC virus as a diagnostic (now seen in <60% cases, probably related to lower JCV viral load in the CNS, itself related to higher CD4 counts). Baseline CD4 count greater than 100 cells/mm3 is still the predominant factor for survival (>90% vs 20% when greater or lower than 100 cells/mm3).

References:
1. Gasnault J, Chavez H, Dorofeev et al. Acceleration of Immune Recovery on Intensified ART Improves Survival in Patients with AIDS-related Progressive Multifocal Leukoencephalopathy: Preliminary Reports of the ANRS 125 Trial. Abstract 379.
http://www.retroconference.org/2007/Abstracts/28936.htm
http://www.retroconference.org/2007/PDFs/379.pdf
2. Clifford D. Progressive multifocal leukoencephalopathy in the era of HAAAT. Oral abstract 119.
The oral overview presentation can be viewed online from the CROI website (see Wednesday, 10.00-12.00am HIV infection in the brain).

Lung cancer risk has been estimated to be two to seven times higher in HIV-seropositive people than in general population. [1, 2] Both prognosis and survival in this group are extremely poor. Several studies looking at the smoking habits of the HIV-seropositive individuals in the US and comparing them with the habits of the HIV-seronegative population attempted to find an explanation for the elevated risk, but the results were quite contradictory, mainly as a result of the fact that the studies included only a small number of cancer cases. [3,4] The data regarding the relationship between the HIV-induced immunosupression (measured by CD4 count) and lung cancer are scarce. [5]

To provide a clearer picture of the situation Chatuvedi AK and colleagues from the Viral Epidemiology and Biostatistics branches of the Division of cancer epidemiology and genetics of the National Cancer Institute in Rockville (US) conducted a study using the AIDS surveillance data on 397 927 HIV-seropositive individuals. [6] That data was linked to population-based cancer registry data in six US states and five metropolitan areas. The published analysis includes the results for adolescents and adults, defined as 15 year old or older at AIDS onset (diagnosed between 1980 and 2002). Cancer cases spanning 60 months prior to and 60 months after the AIDS onset were identified via the cancer registries. Additional emphasis was put on the 4-27 month period after the AIDS onset. Pulmonary occurrences of KS and NHL and cancers with no specific International Classification of Diseases for Oncology codes (8000 to 8005) were not considered lung cancers. There were not enough data on the actual smoking behaviour of the subjects and for this reason plausible hypothetic smoking scenarios were used. In particular the models, developed by Flanders at al, were applied. [7] As the models predict lung cancer mortality, the researchers modified them to predict incidence.

The results showed that lung cancer among the people with AIDS was significantly elevated. In the 10-year period spanning (60 months before and 60 months after AIDS onset), 1489 lung cancer cases were observed. This gives a SIR (standardised incidence ratio) of 1.0 (95% CI, 0.7-1.3; n=42). Lung cancer risk was particularly high during the AIDS onset period, 6 months before to 3 months after AIDS (SIR, 10.5; 95% CI, 9.7-11.4; n=629). Interestingly enough, incidence was higher in men than in women and increased with age, although the SIRs suggest that risk relative to the general population is higher for women and in particular for younger individuals (10.4 for ages 15-29 years). Even though lung cancer risk was high for all HIV risk groups, it was especially high for the IDUs (SIR, 3.9).

Among the observed cancers the predominant type was adenocarcinoma (34%), followed by squamous cell carcinoma (20.8%), and large cell carcinoma (9.9%). The risk of all histologic subtypes was similarly elevated among PWA compared to the general population.

Cancer risk was significantly elevated in all CD4 cell categories, except among PWA with CD4 count >300 mL. Similar analyses performed for the pre-HAART and HAART eras failed to show any relationship with CD4 count in either period.

The observed cancer incidence was again significantly higher among PWA, regardless of the smoking habits. That was specifically true for the PWA in the age range of 40-49 years.

References:

1. Engels EA, Pfeiffer RM, et al., Trends in cancer risk among people with AIDS in the United States 1980-2002; 20:1645-1654
2. Powles T, Nelson M, Bower M. HIV-related lung cancer-a growing concern? Int J STD AIDS 2003; 14:647-651
3. Giordano TP, Kramer JR. Does HIV infection independently increase the incidence of lung cancer? Clin Infect Dis 2005; 40:490-491
4. Hessol NA, Seaberg EC, et al., Cancer risk among participants in the women’s interagency HIV study. J Acquir Immune Defic Syndr 2004; 36: 978-985
5. Mbulaiteye SM, Biggar RG, et al., Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic. Syndr 2003; 32:527-533
6. Chatuvedi AK, Pfeiffer RM, et al., Elevated risk of lung cancer among people with AIDS. AIDS 2007; 21(2):207-213
7. Flanders WD, Lally CA, et al., Lung cancer mortality in relation to age, duration of smoking, and daily cigarette consumption: results from Cancer Prevention Study II. Cancer Res 2003; 63:6556-6562

Christophe Piketty and colleagues looked at the impact of HAART on incidence of anal cancer diagnosed between 1992 and 2003 in HIV-positive patients from the French Database of HIV (FHDH). The analysis looked at pre-HAART, early HAART, and later HAART time periods. 92 cases were identified (84 men, 8 women) from almost 75,000 patients in the database.

Among men, 74% were men who have sex with men. The median age at diagnosis was 42.4 years [IQR: 36.0-49.3]; the median CD4 cell count was 247 cells/mm³ [IQR: 135-420]; the median nadir CD4 cell count was 80 cells/mm³ [IQR: 21-174] and 39% of the cases had presented an AIDS defining event prior to the anal cancer diagnosis. At diagnosis, 71 patients (77%) had been receiving HAART for over five years (median 65 months [IQR: 44-77]).

Table 1: Changes in incidence rate of anal cancer

The incidence of anal cancer increased, in both the whole HIV-cohort, and in HIV-positive men who have sex with men (MSM), though the risk in MSM was approximately twice as high, and is detailed in Table 1. The increase in all rates was explained by the investigators by longer life expectancy conferred by HAART, in that people are living long enough for malignancies to develop. The survival probability after the anal cancer diagnosis was 74%+/-6% at 3 years.

The conclusion drawn by the researchers was that as HAART exhibited no favorable effect on the incidence of anal cancer, this ‘supported the urgent need for developing anal cancer screening programs for HIV-infected individuals’.

Reference

1. Piketty C, Selinger-Leneman H, Grabar S et al. Dramatic increase in the incidence of anal cancer despite HAART in the French hospital database of HIV. XVI International AIDS Conference, Toronto, Canada. 13 – 18 August 2006. Oral abstract TUAB0305.

Mark Bower and colleagues from the Chelsea and Westminster Hospital London, presented a prognostic score for patients diagnosed with Kaposi’s Sarcoma (KS), derived from analysing covariates predictive of overall survival in a cohort of 326 HIV+ patients who developed KS since 1996.

The score in these patients, ranged from 0 to 15 and was calculated starting at the number 10. It incorporated:

• S stage – other ADI: +3 (any other HIV-related illness)
• age: +2 (if >50 years old at diagnosis)
• KS as first ADI: -2 (if KS is the ADI), and
• CD4 cell count: -1 (per 100 cells/mm³ at diagnosis)

Individuals with a prognostic score of 0, 5, 10 and 15, had 1 year survivals of 99.4%, 96.7%, 83.4% and 37.8% and 5 year survivals of 98.4%, 91.8%, 63.1% and 8.4% respectively. Increasing the prognostic score by 1 increased the risk of death by 40% (HR 1.4, 95% CI 1.28-1.53, bootstrapped HR 1.39, 95% CI 1.25-1.51) and the index has a concordance of 76.8% (95% CI 71.7-82.3%). The prognostic index, validated internally using a bootstrap procedure with resampled data, applied to individuals on and off HAART at KS diagnosis.

The study concluded that this score can be used to guide therapeutic options.

Ref: Bower M, Sanitt A, Mazhar D et al. A prognostic index for AIDS-associated Kaposi Sarcoma in the era of highly active antiretroviral therapy. Poster abstract TUPE0046.

Andrew Benzie and colleagues from St Mary’s reported the case of a 38 year old, ARV-naive Portuguese man, who presented in April 2005, with a 6-month history of intermittent episodes of high fever, dry cough and shortness of breath on exertion, which increased in severity with each episode.

CD4 count and viral load were 210 cells/mm³ and 34,000 copies/mL respectively, but CD4% was very low at only 6%.

The abstract details that on ‘admission, he was pyrexial with heptosplenomegaly. He was thrombocytopenic (58 · 109/mL) and had a mild neutrophilia. CRP was 127 mg/L and albumin was low at 25 g/L. Chest X-ray and bronchoscopy were normal. Stains and cultures for Pneumocystis, Cryptococcus and Mycobacterium tuberculosis were negative. Initially, he was treated presumptively for community-acquired pneumonia and PCP. Fever resolved and he was commenced on HAART. His condition again deteriorated with worsening thrombocytopenia, hypoalbuminaemia and oedema and respiratory distress. Plasma tested positive for both EBV and HHV8 DNA by PCR. Castleman’s disease was suspected.

Despite negative investigations including serology, bone marrow aspiration with culture for Leishmania, the patient died and post-mortem revealed extensive pulmonary leishmaniasis.

The researchers concluded that diagnosis of visceral leishmaniasis in HIV infection is difficult as only 40-50% of cases have positive Leishmania serology. Clinicians should have a high index of clinical suspicion for visceral leishmaniasis in patients who present with fever and hepatosplenomegaly, despite negative serology and bone marrow aspiration/culture.

COMMENT

Although Leishmania and HIV co-infection, is rare in the UK, it is increasingly frequent elsewhere, and could arguably be considered an AIDS defining illness, as immune suppression can activate previously latent infection, and HAART reduces risk of relapse after leishmaniasis treatment.

The most accurate diagnosis in HIV-positive patients is obtained by using PCR.

The highest incidence of leishmaniasis, including cases of coinfection, are probably in Central and South America (especially Brazil); North and East Africa; Asia (India, Bangladesh, Nepal) and in Southern Europe (2000 cases of coinfection were reported by 2003 from Spain, Portugal, France, Italy). In Spain 60% cases of leishmaniasis are in HIV-positive individuals, and leishmaniasis is a notifiable disease.

This report is important for doctors treating patients who come from regions where leishmaniasis is endemic.

Ref: Benzie AA, Goldin RD, Walsh J. A case report of seronegative pulmonary leishmaniasis in an HIV-hepatitis C co-infected patient. Abstract P100.

One small poster went virtually unnoticed and unreported. Cryptosporidium in the pre-HAART era was one of the principle causes of debilitating diarrhoea, malabsorption and wasting. It is one of the reasons for recommending bottled water or boiled water, and although tap water is treated to routinely remove crypotosporidium, occasional outbreaks of water contamination still causes health alerts. Infection commonly results in 2-3 weeks of diarrhoea until the body clears the parasite naturally, but it causes more serious problems for people with impaired immune systems including the elderly, young children and people with HIV.

Joe Gathe and colleagues from Texas presented results from a small prospective open label study using the antibiotic rifaximin in five patients with symptomatic cryptosporidial diarrhea and CD4 <20 cells/mm³.

Symptomatic cryptosporidiosis was proven by stool analysis in all patients, who had a range of 6 to 15 stools/day for 2-6 months, without successful treatment. All required hospitalisation for weight loss and dehydration and had significant coinfections including CMV, bacterial sepsis/arthritis, campylobacte, giardiasis, disseminated CMV infection, cryptosporidial cholecystitis and mycobacteria tuberculosis.

Multiple anti-cryptosporidial interventions had failed in 3/5 patients. All patients received rifaximin 400mg p.o. BID with diarrhea control within one week and organism eradication in 2-8 weeks. None of the patients received effective HAART over the treatment period. Relapse/recurrence was not seen over 1-7 months despite 4/5 patients continuing with CD4 <50 cells/mm³.

This was a small, uncontrolled study, but the authors concluded that immediate larger studies of rifaximin for cryptosporidial gastrointestinal disease in HIV patients are warranted.

COMMENT

This is an interesting study, but similar small studies or case reports wth paromomycin, albendazole and even casein could not be confirmed in controlled studies.

Rifaximin (Xifaxin) is a rifamycin marketed by Salix, with an indication for treatment for travellers diarrhoea caused by noninvasive strains of Escherichia coli. Although only approved in the US in May 2004, it has been available in Europe for many years. Several posters at ICAAC referred to ongoing research with rifaximin as a treatment for for clostridium difficile. [2, 3]

As cryptosporidium is often difficult to isolate, and rifaximin produced a rapid reduction in symptoms, this option could be considered already for patients with persistent diarrhoea. Activity against microsporidia should also be considered.

References:

1. Gathe J, Smith K, Mayberry C et al. – Cure of severe cryptosporidial diarrhea with rifaximin in patients with AIDS. 10 EACS Poster11.3/1.
2. Kokkotou K, Mustafa N, O’Brien M et al. Rifaximin: a Novel Non-Absorbed Antibiotic Therapy for Clostridium difficile- Associated Diarrhea (CDAD). 45th ICAAC, Washington 2005. Abstract B-35-78.
3. Louis TJ. Treating Clostridium difficile in the Future: What’s Coming? 45th ICAAC, Washington 2005. Presentation 1774.

A prospective 1 year (2004 to 2005) cohort study investigated immunity against varicella zoster virus (VZV) in HIV-seropositive migrants from sub-Saharan Africa. VZV is ‘an almost ubiquitous, genrally mild’ infection in Western Europe, but is less prevalent in Africa. VZV serology was recorded and analysed, together with patient demographics, including age, sex, parity, and CD4 count, in 278 newly HIV-diagnosed individuals at St James’ Hospital in Dublin. 182/278 subjects were Western European and among them only 6 (3.3%) had negative VZV.

Of the non-nationals, only 18 had a negative serology (p<0.01) indicating non-immunity prevalance of 18.75% in this group. These results show clearly that the sub-Saharan population has lower immunity to VZV, and that HIV-seropositive patients from this geographical background are more at risk of developing the infection.

Ref: Pallin M., Loy A., Coughlan S., Bergin C., Mulcachy F., Decreased varicella zoster immunity in migrants from sub-Saharan Africa. 10th European AIDS Conference/EACS, November 17-20, 2005, Dublin, Ireland. Abstract PE18.5/1.

An interesting case study presented as a poster at the meeting, detailed how a 36 year old man from South Africa who started HAART in November 2002, was forced to start and stop treatment five times. A short time after treatment was started, vomiting, diarrhoea and stomach cramps occurred to a sufficiently severe and unmanageable extent that treatment was stopped. Repeating this sequence a further four times strengthened the association between HIV-treatment and symptoms.

However, colonic histology showed numerous granulomas containing ova of Schistosomiases mansoni. Schistosoma antibody ELISA was positive at level 4, and he was successfully treated with praziquantel.

The researchers suggested that this patient was infected many years earlier, but only experienced symptoms after immune reconstitution resulted in an acute inflammatory response to chronic infection. Schistosomiases is the second most prevalent tropical disease, with over 120 million symptomatic people worldwide. Awareness of this potential immune reconstitution symptom may be relevant both for clincians who are treating patients in the UK and as ARV treatment becomes more available in tropical countries.

Ref: deSilva S, Walsh J, Brown M. The snail’s progress: a case report of schistosomiasis in the era of HAART. 11th Annual BHIVA Conference, 20-23 April 2005, Dublin. Poster P62.

Three randomised placebo-controlled studies presented in Glasgow demonstrated the usefulness of nandrolone decanoate (ND) in combating weight loss of HIV-positive men.

One found that ND increased body weight in subjects when compared to placebo or testosterone; a second trial found that two higher doses of ND were more effective than a lower dose or placebo; and a third trial concluded that ND was better than placebo but little different from recombinant human growth hormone (rhGH) in its ability to increase lean body mass in the subjects.

ND was found to be well tolerated in all thee studies and there were no dose-related responses observed in quality of life (QoL) or in change of CD4 or CD8 cell counts.

Julian Gold and colleagues in Australia and the Netherlands carried out an international multi-centre double-blind trial comparing ND with placebo and testosterone (TST). [1]

This study randomised 303 subjects to ND150mg, TST 250mg or placebo fortnightly for 12 weeks. Those treated with ND showed significantly greater increases in fat free mass (FFM) versus those given placebo. Increases in weight were significantly greater with ND than with TST. The researchers found no significant differences in the incidence of adverse events, in immune markers or in HIV viral load.

Chris Duncombe and colleagues of the Netherlands Austria Thailand (NAT) Research Collaboration, report on their multicentre double-blind trial that looked at the effects of treatment with ND 50mg, ND 100mg and ND 150mg or placebo in 91 subjects over 24 weeks. [2]

The two groups on the higher doses of ND showed a mean increase in LBM compared to placebo. At week 12, those on placebo and those on ND 50mg had lost weight, while the 100mg and 150mg groups of ND showed weight gain of 0.59kg and 0.76kg respectively. QoL was measured using the MOS-SF30 questionnaire and no dose related responses were observed. Dose did not affect CD4 or CD8 cell counts.

Theodorus Geurts and colleagues in the Netherlands and the United States, randomised 85 patients to receive 12 weeks ND 150mg or placebo, fortnightly and double blind, or open label rhGH 6mg daily. [3]

They noted significantly greater gain in lean body mass after 12 weeks of ND treatment compared to placebo but there was no significant difference between ND and rhGH. There was significantly greater loss of fat mass after rhGH than after ND, and no difference between ND and placebo. FFM, body cell mass and intracellular water were also seen to increase significantly more with ND than placebo. The rhGH group suffered more drug-related adverse events than either of the other two groups.

Comment

The first two studies confirm benefits reported anecdotally for many years but it is good to see this confirmed in randomised controlled settings.

The use of 6mg rHGH in the Dutch study, is associated with considerable side effects. Some US practicioners currently recommend <2mg/day rHGH in combination with testosterone replacement and/or oxandrolone.

References:
1. Gold J, Batterham M, Helmyr P et al. Nandrolone decanoate compared with placebo and testosterone for HIV associated wasting: a multi-centre international clinical trial. 7th ICDTHI,14-18 Nov, 2004, Glasgow. Abstract PL7-5.
2. Duncombe C, Chuenyam T, Geurts P et al. The effects of nandrolone decanoate on weight loss and quality of life in male patients with acquired immunodeficiency syndrome. 7th ICDTHI,14-18 Nov, 2004, Glasgow. Abstract PL7.6.
3. Geurts T, Storer T, Woodhouse L et al. Randomised, placebo-controlled trial of nandrolone decanoate in HIV-infected men with mild to moderate weight loss with rhGH as reference treatment. 7th ICDTHI,14-18 Nov, 2004, Glasgow. Abstract P8.

In this study, Australian researchers analysed the clinical features and predictors of survival for AIDS-related non-Hodgkin’s lymphoma (NHL) in the era of HAART, compared to earlier in the HIV epidemic.

All AIDS-NHL cases diagnosed at three inner Sydney hospitals caring for people with AIDS during 1985-2001 were identified through medical record searches. Demographic, clinical, immunological and histopathological information was recorded. Year of NHL diagnosis was grouped into three periods, corresponding to whether monotherapy (1985-1991), dual therapy (1992-1995) or HAART (1996-2001) was the main treatment for HIV infection. Statistical comparisons were made between the pre-HAART and post-HAART eras.

Three hundred cases of AIDS-NHL were identified. Divergent trends were identified for systemic and primary central nervous system (CNS) NHL. For systemic NHL, the CD4+ T cells count at NHL diagnosis increased markedly to 208 cells/mm3 in the post-HAART era (P=0.014) and there was a trend towards presentation as the first AIDS-defining illness (69%, P=0.053), and as earlier stage NHL disease (42%, P=0.048). Median survival time increased from 4.2 months in 1985-1991 to 19 months in the post-HAART era (P<0.001).

In a multivariate model, predictors of poor survival from systemic NHL included: NHL diagnosis after another AIDS-defining illness (P<0.001), stage 4 NHL (P<0.001), presentation at extra lymphatic sites (P=0.001), and non-receipt of chemotherapy (P=0.002).

After adjusting for the factors, those diagnosed in the era of HAART had a significant 56% reduction in rate of death (P<0.001). In contrast, for CNS NHL, clinical features were little changed and survival did not improve in the era of HAART.

The study concluded that systemic NHL is presenting earlier in the course of HIV disease, and at a less advanced NHL stage. There has been a marked improvement in survival in the era of HAART even after adjustment for other prognostic variables. In contrast, primary CNS NHL remains a disease that presents late in the course of HIV infection and is associated with a very poor prognosis.

Source: HIVandHepatitis.com

© Copyright 2004 by HIV and Hepatitis.com. All Rights Reserved. Reproduction for personal or educational use is encouraged and does not require permission. Written permission is required to re-print copyrighted articles but is almost always granted (email publisher@HIVandHepatitis.com).

http://www.hivandhepatitis.com/recent/malignancies/092404_f.html

Ref: Robotin MC et al. Clinical features and predictors of survival of AIDS-related non-Hodgkin’s lymphoma in a population-based case series in Sydney, Australia. HIV Medicine 5(5): 377-384. September 2004.

Veiga and colleagues from Brazil reported response rate by CD4 count to hepatitis B vaccination in 55 HIV-positive patients and 20 HIV-negative controls, who had received 3 doses (0, 30 and 180 days) of recombinant DNA hepatitis B vaccine. [1]

The overall HBV vaccine seroconversion rate was 59% (32/55) for HIV+ group, and 100% the 20 controls. Response rate by CD4 count at the time of vaccination were 81%, 65% and 25% in patients with >500, 200-499 and <200 cells/mm³ respectively.

The median CD4+ count at the time of vaccination among responders was 452 cell/mm³, significantly higher than in non-responders (359 cells/m³, 20%, p=.03). Memory T CD4+ cells were also significantly (p=.04) higher in responders (255 cells/mm³) than in non-responders (178 cells/mm³). In addition, viral load at the time of immunisation was significantly (p=.03) higher in non-responders (3.63 log10) than in responders (2.86 log10). Seven HIV-1-infected patients experienced a significant viral load increase, transient in five cases.

Response to HBV vaccine by CD4 count at vaccination (anti-HBs>10 UI/L)

However, a larger study from Overton and colleagues at the Washington University School of Medicine, did not find a link with vaccine response and CD4 count. [2]

Of 342 recipients of regular 3-dose HBV vaccination programme, 149 subjects had complete data for evaluation; 35.6% were male, with a mean age of 34.3 years and baseline CD4 + T cell counts 429 cells/mm³

In this cohort, only 18 patients (12.1%) developed protective HBsAb (> 10mIU/mL).

Baseline characteristics and timing of vaccine administration were not statistically different among responders and non-responders. Factors associated with a protective antibody response included male gender (p=0.001), older age (p=0.002), and an HIV plasma RNA level < 400 copies/mL at time of vaccination (p<0.001). Neither the CD4 cell counts at time of vaccine nor preceding CD4 cell nadir was predictive of successful response.

A strategy to improve response rates was suggested in a study by Fonseca and colleagues from University Medical School of Sao Paulo. This group randomised 210 patients to use either standard (20ug) or double dose (40ug) (given at 0, 1, 6 months, IM) to see whether this would increase response rates. [3]

Response rate (anti-HBs >10mIU/mL) was 47% for the double dose and 34% for the standard dose. A logistic regression model, showed a statistically significant higher seroconversion rate with the double dose, a history of HIV heterosexual exposure, CD4 cell counts >= 350 and HIV viral load < 10,000 copies/mL.

This study concluded that the best current strategy for a HBV vaccine response in HIV patients would be to use a double dose as a primary series when the viral load is likely to be low and when there is likely to be an adequate immune response. This might be early in the course of infection or following successful HAART.

A second study from Brazil, reported response rate of 47% using the double-dose strategy, and that responders had significantly higher CD4 counts than non-responders. However the study abstract contained no further breakdown by CD4 levels. [4]

References:
1. Veiga APR, Casseb J, Duarte AJS – Efficacy to hepatitis B vaccination and its relationship with T CD45RA+ (naive) and CD45RO+ (memory) subsets in HIV-1-infected subjects. XV Intl AIDS Conference, Bangkok. Abstract B10392.
http://www.ias.se/ejias/show.asp?abstract_id=2170874
2. Overton ET, Sungkanupargh S, Seyfried W et al. Protective immunity after hepatitis B vaccination in HIV-infected persons: Does an undetectable HIV RNA level predict success? XV Intl AIDS Conference, Bangkok. Abstract MoPeB3284.
http://www.ias.se/ejias/show.asp?abstract_id=2171751
3. Fonseca MO, Pang LW, 2, Cavalheiro NP et al. Randomised trial of recombinant hepatitis B vaccine in HIV-infected adult patients comparing a standard dose to a double dose. XV Intl AIDS Conference, Bangkok. Abstract MoPeB3312.
http://www.ias.se/ejias/show.asp?abstract_id=2175659
4. Conference Góngora DVN, Góngora-Rubio F, Onishi E et al. Serological responses to hepatitis B vaccination in HIV infected patients. XV Intl AIDS Conference, Bangkok. Abstract B10109.
http://www.ias.se/ejias/show.asp?abstract_id=2169929

The introduction of increasingly effective antiretroviral drugs has resulted in increased survival of patients with HIV-infection. Prior to the availability of such drugs the development of HIV-associated dementia (HAD) was a much feared and serious consequence of advancing HIV disease. The precise impact of HAART on HAD and the associated cognitive dysfunctions remains, however, to be fully determined.

In the pre-HAART era the mean CD4 count at the time of diagnosis of HAD was 50–100 cells/mm3. Post 1996 and the introduction of more effective ARVs this has risen to around 160 cells/mm3. The reason for this elevation is unclear but both the nadir CD4 cell count and disease duration are likely confounding variables in the current HAART era.

Changes in the natural history of HAD have also been noted. In the pre-HAART era the mean time from diagnosis to death was six months, this has now been lengthened to 44 months. A consequence of such prolonged survival is that the prevalence of HAD is actually increasing. There is also a suggestion that the actual cognitive deficit in HAD may be changing with the increasing use of HAART – involving more cortical type abnormalities and less basal ganglia. The fact also remains that HIV encephalopathy continues to be present in 25% of patients at autopsy, a rate that has not changed since the widespread use of HAART.

Data presented at the 11th CROI provided some additional clues as to how HAD is now manifesting in those patients receiving more effective antiretrovirals.

Neurocognitive impairment in HAART treated patients and survival

Before the introduction of HAART, HAD was recognised as an independent risk factor for death. Tozzi and collegues from the National Institute for Infectious Diseases, Rome, Italy presented prospective data on mortality among patients referred for neuropsychological examination since 1996. [1]

On testing, of 432 enrolled subjects, 238 (55.1%) were found to be neurocognitively impaired and 194 (44.9%) unimpaired. All subjects were treated with HAART regimens which were changed accordingly with the availability of new drugs and by individual patient response. Median follow up period was 32.4 months and overall 47 deaths were recorded – 38 among impaired and 9 among unimpaired patients.

At enrolment neurocognitively impaired and unimpaired patients did not differ in terms of gender, plasma viral load, or positive HBV surface antigen. However, impaired subjects were older, less educated, had a lower CD4 cell count, more advanced HIV disease, higher prevalence of intravenous drug use, higher prevalence of HCV and showed a higher rate of virological failure during subsequent HAART regimes.

Differences in survival according to neurocognitive status were assessed by means of the Kaplan-Meier method and by the Cox proportional hazard model. After 84 months of follow-up the estimated survival proportions were 68.5% in the impaired group and 84.9% in the unimpaired group (p<0.01). After adjusting for confounding variable the multivariate analysis revealed that neurocognitively impaired patients still showed an increased risk of death as compared to unimpaired patients (HR=2.4; 95% CI: 1.1 – 5.1).

After stratification for virological response to HAART, the estimated risk of death for impaired patients was still significantly higher among the subgroup with virological failure (HR=2.9), but no longer significant among the subjects with durable virological suppression (HR=1.0).

The authors conclude that “Among HIV-positive patients receiving HAART, patients with HIV-associated neurocognitive impairment had an independent and statistically significant higher risk of death then subjects without neurological impairment. …this highlights the clinical relevance of HIV-related CNS involvement even in the HAART era.”

The association between neurocognitive impairment and virological failure revealed in this study requires further investigation. Might impairment be a predisposing factor for poor adherence?

HIV dementia, aging and HAART

Age is a suggested risk factor for the development of HAD. With increasing survival rates aging is a real possibility for many with access to effective antiretrovirals. Would increasing age also, therefore, lead to increased risk of HAD, even if viral replication is suppressed?

Lorenzini and colleagues, again from Italy, attempted to answer this question using a nested longitudinal study on a national cohort of HIV-positive patients with neurological diseases. [2]

From 2000 to 2003, 195 patients with HIV encephalopathy were notified (these consisted of 53% HAD, 47% MCMD – Minor cognitive motor disorder). The overall prevalence was 21% with an increasing annual rate. Median age was 42 years and a previous ARV exposure was present in 45%, 28% were receiving HAART at diagnosis.

Stratifying patients according to age and exposure to antiretrovirals, among naïve patients the prevalence of HIV encephalopathy was higher in older subjects: 13.7% (20-39 years), 28.3% (40-49 years), and 37.5% (≥50 years). The same proportions for HIV dementia were 7.2%, 15.3%, and 27.3%. Among ARV-experienced patients no significant increase of HIV encephalopathy or HAD for older age was observed. An increased prevalence of HIV dementia among older naïve patients compared to older experienced patients was detected (p = 0.05).

The investigators concluded “…HAART appears to change the relationship between aging and developing HIV dementia, conferring a neuroprotective effect to older patients and affecting the increased prevalence rate of HIV dementia with increasing age.”

Can HAART improve cognitive function and do drugs need to reach the CNS?

It has been hypothesised by a number of researchers that neuropsychological impairment might progress despite virological and immunological response to ARV’s. Poor CNS penetration of active agents and ongoing viral replication in a CNS “sanctuary” site may be one possible reason for continuing cognitive decline. Data on the natural history of HAD and cognitive function from longitudinal studies of those treated with effective ARV’s is scant.

ACTG 362 started life as a study of prophylaxis intervention for MAC. After the impact of HAART made MAC prophylaxis extremely unusual the study was converted into an observational cohort of advanced AIDS patients (CD4 < 50 before entry). [3] A series of annual cognitive evaluations using three simple tests assessed speed of information processing, mental flexibility and working memory. At study entry most participants were immune reconstituted (mean CD4=230) and HIV suppressed (65% < 500 with only 14% >20,000 RNA copies/mL).

Prevalence of neuropsychological impairment (NPI) was estimated at 40% in advanced AIDS patients after prolonged immunological reconstitution on HAART. In addition, better performance was associated with continued or recently improved suppression of plasma HIV RNA levels, and was unrelated to CD4 count. In a univariate model of change, NPZ3 score (Z-scores of Digit Symbol Substitution and Trailmaking A and B) improvement was associated positively with plasma HIV RNA suppression (<500) at time of testing or suppression of HIV (>500 to <500) over the prior 16 weeks. Interestingly lowest lifetime CD4 count (nadir) did not correlate with changes in NPZ3 score.

It was concluded from these data that “…plasma HIV suppression appears to be critical to improvement of cognitive function” and that “…most advanced AIDS patients responding to HAART for prolonged periods do not experience detectable cognitive decline.”

Two separate studies presented in poster form addressed the question of whether there is any additional benefit for cognitive function from drug regimens containing ARV’s thought to have better CNS penetration. Caution must be observed in interpretation as one study was cross sectional [4] and the other had small numbers of subjects who were not antiretroviral naïve [5]. The cross sectional study revealed that 50.3% of subjects had abnormal neuropsychological performance.

The number of CSF penetrating drugs within each regimen was not correlated with neuropsychological performance. Indeed, the only HIV-related factor independently associated with neuropsychological disorder was plasma HIV-1 replication. The separate, prospective study compared neurological functioning between patients failing HAART placed on regimens containing at least one CNS penetrating agent to those with non-penetrating regimens.

Overall there was a significant improvement in neurological functioning at follow-up. However, no significant differences were found between 10 subjects with CNS penetrating regimens compared to 19 subjects on non-penetrating regimens. Both studies, therefore, found that effective virological suppression (measured by plasma HIV RNA) appeared to be more important than whether or not the regimen contained a CNS penetrating antiretroviral.

AIDS dementia complex, Alzheimer’s disease and ongoing brain injury despite HAART

In perhaps the most disturbing presentation on CNS effects of HIV, Michael Weiner presented the results of his groups work on structural brain changes at the late breaker session [6]. This controlled, longitudinal study used structural MRI, MR spectroscopy, neuropsychological testing and EEG evoked response with measurement taking place with a two year interval. Both HIV-positive and HIV-negative subjects were studied with these groups being divided into heavy or light drinkers to control for the known effects of alcohol intake. A total of 128 participants took part.

The structural MRI results showed that over two years the HIV-positive subjects (all of whom were receiving ART) had greater rates of ongoing white matter loss than the controls (p=0.0013). The annual loss of white matter between HIV-positive and HIV-negative patients who were light drinkers was 1.2% and -0.6%, respectively (p=0.003). White matter atrophy was also found to be greater in those HIV-positive patients with higher viral loads when compared to HIV-negative patients. Subjects with viraemia had significantly greater annual loss of white matter compared to those with good suppression of HIV replication (1.3% vs. 0.6%, respectively; p=0.06). However, no significant differences were found between patients with suppressed infection and HIV-negative controls. No differences were found between the groups with regard to cognition or EEG-evoked response.

The study authors concluded that the rates of ongoing white matter atrophy, although significantly different from controls, were small and not accompanied by progressive cognitive impairment. They did caution, however, that the results suggest that even HAART treated individuals do have ongoing brain damage. Additionally, these effects over a number of years would be expected to produce cognitive impairment similar to that observed in Alzheimer’s disease.

The development of Alzheimer’s disease itself is also becoming an increasing concern for researchers and clinicians caring for those with HIV-infection. Increased age, high lipids, axonal injury and the effects of tat and quinolinic acid on the brain all point to a theoretically increased risk of Alzheimer’s disease in HIV-infection [7].

Further data on the relationship between Alzheimer’s disease and HAD was presented by Bruce Brew at this meeting [8].

As a marker for the increased risk of Alzheimer’s cerebrospinal fluid (CSF) was examined for the presence of reduced amyloid beta 1-42 or increased amyloid beta tau (both of which are related to excess amyloid beta production). All subjects were HIV-positive patients with AIDS Dementia Complex. In total 25 patients CSF was analysed and the results revealed that amyloid beta 1-42 levels were significantly lowered and in the same range as those found in Alzheimer’s Disease.

The researchers conclude that “…AIDS Dementia Complex may be complicated by an illness that at least at the biochemical level is similar to Alzheimer’s Disease. Moreover, it raises the possibility that HIV patients in general may be at increased risk of Alzheimer’s.”

References

Unless stated otherwise, all abstract references are to the Program and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (11th CROI). February 8-11, 2004. San Francisco, CA.

1. Tozzi, V et al. Neurocognitive impairment and survival in HIV-positive patients treated with HAART: results from an urban observational cohort. Abstract 507.

2. Lorenzini, P et al. HAART Modified risk of HIV dementia associated to increasing age. Abstract 489.

3. McCutchan, A et al. Improved cognitive function in immune reconstituted advanced AIDS patients is associated with maintenance of HIV suppression. Abstract 498.

4. Antinori, A et al. Antiretroviral drugs penetrating CSF do not influence neurocognitive performance in HIV-1-infected patients responding to HAART. Abstract 508.

5. Robertson, K et al. Neurological functioning and CNS penetrating antiretroviral regimens. Abstract 501.

6. Weiner, MW et al. Progressive white matter loss suggests ongoing brain injury in ART-treated HIV+ patients. Abstract 33 LB.

7. Brew BJ. Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. Aids 2004,18 Suppl 1:S75-78.

8. Brew, B et al. Relationship between Alzheimer’s disease and AIDS dementia complex. Abstract 472.

A study of 19 people (73% on HAART) with HIV-associated oral hairy leukoplakia (OHL) and Epstein-Barr virus (EBV) replication found that treatment with high dose oral valacyclovir (Valtrex), one gram every eight hours for a month, could inhibit productive replication of EBV. Walling and colleagues at the University of Texas report that in the majority of cases OHL was resolved and EBV replication was halted.

OHL was cleared in 89% of subjects. OHL and EBV replication recurred in two subjects and EBV replication alone was detected in two more subjects. The researchers theorise that either the virus developed resistance and/or subjects did not take their medication as directed.

According to the research team: “Valacyclovir appears to be a generally safe and effective option for the short-term treatment of OHL in HIV-infected patients.”

Ref: Walling DM, Flaitz CM and Nichols CM. Epstein-Barr virus replication in oral hairy leukoplakia: response, persistence, and resistance to treatment with valacyclovir. J Infect Dis. 2003 Sep 15;188(6):883-90.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12964120&dopt=Abstract

Partly because of their weakened immune systems, people with HIV/AIDS (PHAs) are at increased risk for certain tumours such as non-Hodgkin’s lymphoma and Hodgkin’s lymphoma. These tumours occur when cells of the immune system, mostly B cells, begin to multiply abnormally. Signs/symptoms of lymphoma can include unexpected tiredness, unintentional weight loss, fever, night sweats, swollen lumps in the neck, groin, or under the arms.

To help make a diagnosis of lymphoma, several procedures and tests are needed, including detailed pictures from inside the body using CAT scans or MRIs, blood tests, and biopsies of the tumour.

Lymphoma and HAART

In the time before highly active antiretroviral therapy (HAART) became available in high-income countries, the chances of survival after a diagnosis of AIDS-related lymphoma were low. Even with anti-cancer therapy, the average PHA survived for about six months. Now that HAART is available, survival after a diagnosis of lymphoma has been extended. In one study from France, researchers found that, on average, survival in the time of HAART rose to about 20 months after a lymphoma diagnosis. Moreover, researchers are testing new anti-lymphoma regimens, such as EPOCH, which appear to result in high rates of remission. For more details about EPOCH, please see CATIE’s TreatmentUpdate 136 available at:

http://www.catie.ca/tu.nsf

While this statistic is encouraging, the fact remains that some PHAs with lymphoma only experience a partial remission or may not go into remission when first treated for cancer. To deal with this situation, researchers at several Italian hospitals have been testing a combination of stem-cell (CD34+) transplants and high-dose chemotherapy in 16 PHAs with lymphoma. Their results, published in the 1 December issue of the Journal of Clinical Oncology, suggest that these treatments can help some PHAs recover from cancer when first-line chemotherapy fails.

Why transplant stem-cells?

In addition to damaging tumours, chemotherapy damages the bone marrow – the site of blood cell production. So the doctors in this study came up with the idea of giving a stem-cell transplant to the subjects. Why stem-cells? Most cells in the body are specialised, for example, nerve cells, liver cells, skin cells and so on. But stem-cells are unspecialised cells that can turn into other types of cells. In the case of CD34+ stem-cells found in the blood, these can migrate to the bone marrow and turn into cells that specialise in producing other blood cells. By giving patients a transplant of their own stem-cells (collected before chemotherapy), doctors can then use a higher-than-normal dose of chemotherapy to achieve more intensive anti-cancer effects and not greatly worry about bone marrow damage in their patients. This combination of high-dose chemotherapy and stem-cell transplants is used in HIV-negative cases of lymphoma that do not respond to chemotherapy alone.

Before receiving high-dose chemotherapy, patients are given injections of the bone marrow stimulant G-CSF (granulocyte-colony stimulating factor, filgrastim, Neupogen). A few days later, stem-cells are collected from the blood and stored. After chemotherapy, the stem-cells are infused intravenously and they migrate to the bone marrow where they help it to recover and resume producing healthy blood cells.

Study details

Researchers recruited subjects between September 2000 and April 2003. All had AIDS-related lymphoma and had not experienced sustained remission with prior chemotherapy. The profile of the 16 subjects (two female, 14 male) at the start of the study included median age 39 years and CD4+ count 236 cells/mm3. Fourteen subjects were using HAART.

Upon entering the study, subjects received a course or two of normal-dose chemotherapy. The purpose of this was to assess if their tumours would respond to the treatment. If tumours did respond, this chemotherapy served to shrink them prior to exposure to much higher doses of chemotherapy. Once their bone marrow recovered from this round of chemotherapy, stem-cells were collected. At least one month after stem-cells were collected, subjects then received high-dose chemotherapy for a week. The drugs used for the high-dose regimen were carmustine, cytarabine, etoposide and melphalan.

Stem-cells were re-infused into subjects and one week after chemotherapy began, subjects were given the bone marrow stimulant G-CSF. In addition, doctors also prescribed several medications to suppress the development of bacterial, fungal and viral infections. All subjects remained on HAART while in the study.

Results

Six of the 16 subjects in this study did not receive a stem-cell transplant. Three subjects, two of whom had less than 100 CD4+ cells, died from rapidly worsening lymphoma. The bone marrow of three subjects was unable to produce stem-cells despite stimulation with G-CSF.

The research team reported initial results from nine of the 10 subjects (the 10th patient wasn’t enrolled for a long enough time). Seven patients had a complete response (tumours disappeared) and two had a partial response (tumours shrank but did not disappear). About one year after having received a stem-cell transplant, six of the nine subjects remained alive. Most subjects experienced moderate or severe nausea/vomiting, diarrhoea and inflammation inside their mouths.

Because chemotherapy weakens the bone marrow, levels of disease-fighting cells are temporarily reduced and it is not uncommon for cancer patients receiving chemotherapy to develop infections. In this study, two subjects developed fungal infections in their throat and two subjects developed shingles.

Although CD4+ counts fell after high-dose chemo (to an average of 93 cells), by the sixth month of the study they rose to an average of 183 cells. Except for a few days when subjects stopped taking HAART because of side effects from chemotherapy, the average viral load remained below the 50 copy mark.

The researchers noted that six of the 10 subjects remained free from lymphoma for one year after receiving high-dose chemotherapy and a stem-cell transplant. Although the researchers found the results of this study promising, they caution that additional studies with longer monitoring times are needed to confirm and extend their results. Nonetheless, they suggest that high-dose chemotherapy can safely be given to HIV positive people with lymphoma. Although their research was about “salvage” therapy, because of the promising results the research team suggests that high-dose chemotherapy and stem-cell transplants be considered for use earlier in the course of AIDS-related lymphoma, as has been suggested for HIV negative people with lymphoma.

References:

1. Breen EC, Boscardin WJ, Detels R, et al. Non-Hodgkin’s B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype. Clinical Immunology 2003 Nov;109(2):119-129 .

2. Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood. 2001 Oct 15;98(8):2339-44 .

3. Re A, Cattaneo C, Michieli M, et al. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol. 2003 Dec 1;21(23):4423-7 .

4. Zinzani PL, Tani M, Gabriele A, et al. High-dose therapy with autologous transplantation for aggressive non-Hodgkin’s lymphoma: the Bologna experience. Leukemia & Lymphoma 2004;45(2):321-326.

Copyright © 2003 – Treatment Update. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Community AIDS Treatment Information Exchange, Suite 420 – 517 College Street, Toronto, On M6G 4A2 Canada

http://www.catie.ca

Valacyclovir is a more effective prophylaxis than acyclovir against recurrent herpes simplex in HIV-positive people, according to an international placebo-controlled trial.

The study could have significant influence on clinical practice because the researchers conclude that they have established an important treatment option for the management of genital herpes in HIV-positive patients, in the form of a convenient, twice-daily regimen that is well-tolerated.

Intravenous administration of acyclovir has previously been shown to be effective against mucocutaneous herpes in profoundly immunocompromised patients, and oral acyclovir has been shown to suppress genital herpes in a healthy population. Valacyclovir was developed to improve the bioavaliablity of acyclovir.

Two hundred and ninety-three positive subjects on stable antiretroviral regimens, with histories of symptomatic recurrent genital herpes, were enroled in the randomised, double blind, placebo-controlled, multicentre trial in the United States, Canada and the United Kingdom.

The trial compared valacycolvir administered at 500mg twice daily with placebo, and was conducted between May 1999 and January 2002. Subjects were randomised in a 2:1 allocation (valacyclovir to placebo) to receive treatment for up to six months. They were instructed to return to the clinic monthly and at first recurrence of genital herpes. Study drug was discontinued for subjects with clinically confirmed recurrence and they were treated with valacyclovir (1g twice daily) until they were healed. After treatment, they resumed suppressive therapy with open-label valacyclovir.

Of the 231 subjects who completed the study, 89 had a recurrence of genital herpes during the double blind phase of the study: 56/99 (57%) in the placebo group and 33/134 (17%) in the valacyclovir group. The proportion of subjects who had no recurrence of genital herpes at six months was significantly higher in the valacyclovir group than in the placebo group: 65% versus 26% (relative risk 2.5, 95% confidence interval [CI], 1.8-3.5).

The time to first recurrence of genital herpes was a median 59 days in the placebo group, compared with a median >180 days in the valacyclovir group (hazard ratio [HR] 5.0, 95% CI, 3.30-7.7).

Fifteen per cent (15/99) of subjects who received placebo, compared with 4% (8/194) of subjects who received acyclovir, reported a recurrence of oral herpes during the study.

Adverse event rates per exposure day were similar between treatment groups during the double blind phase: 2.2% for the placebo and 2.0% for valacyclovir; and a Kaplan-Meier plot of the time to first adverse event demonstrated a similar incidence in adverse events over time. Three serious adverse events, all in the same subject, were considered to be attributable to valacyclovir.

Fifty HSV-2 isolates were obtained from 48 subjects who had recurrence of genital herpes (but no pretreatment isolates were collected and no HSV –1 was isolated from genital specimens) and acyclovir resistance isolates were identified in three subjects (6.0%), all of whom had CDC stage C HIV disease. Two subjects in the valacyclovir group had a recurrence of genital herpes caused by a resistant isolate after three and 10 weeks respectively, of valacyclovir. One of these had received suppressive antiherpetic therapy, for about one year prior to the study. The third subject, who was in the placebo group but had received suppressive antiherpetic therapy for about four years prior to study entry, had a recurrence of genital herpes caused by a sensitive isolate after four weeks of doubleblind medication and a second recurrence caused by a resistant isolate after about 18 weeks of open label valacyclovir. All three people responded to a five day course of valacyclovir (1g twice daily).

In their discussion, the authors write: “It is believed that most physicians and patients will be reluctant to initiate long-term suppressive therapy for a low recurrence rate of one or two outbreaks per year. A rate of three or more recurrences per year would probably more resemble the use of long-term suppressive therapy in clinical practice. To increase the probability of reaching an end-point in our six-month study, subjects were required to have had a history of four or more recurrences during the previous year. In addition, when considering patients for suppressive therapy in clinical practice, the decision should not be based on the frequency of recurrences alone. The severity of recurrences and the potential for the activation of HIV in this patient group are also important factors.”

Ref: DeJesus E, Wald A, Warren T et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus infected subjects. The Journal of Infectious Diseases 2003;188:1009-1016.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14513421&dopt=Abstract

http://www.journals.uchicago.edu/JID/journal/issues/v188n7/30742/30742.html

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Although a head-to-head study has not been performed against acyclovir, valacyclovir has several advantages over acyclovir. It requires fewer pills and is potentially more effective, but is also more expensive than off-patent acyclovir.

Valacyclovir is also active against HIV–associated oral hairy leukoplakia (HLP) and Epstein-Barr virus (EBV) – See Journal of Infectious Diseases, 2003;188:883-890.

Two studies highlighted the problems of rectal disease in HIV-positive patients, with one study showing anal infection by Human Papillomavirus (HPV) to be almost universal in men infected with HIV. The second study concluded that routine rectal Pap screening is feasible and warranted as part of HIV primary care.

Fortin and colleagues in Montreal, Canada, and at Roche Molecular Systems in California, USA, found anal HPV DNA in 135 (97.8%) of 138 anal samples from 113 men. [1] They also found that anal HPV infection was often caused by multiple HPV genotypes and that high-grade anal intraepithelial lesions (AIN) contained a greater burden of different types.

The most frequent genotypes identified were types 16, 6, 52, 45 and 18 found in 58, 47, 52, 45 and 18 men respectively. Of the newer types studied, four were detected in at least 20 specimens (types 61, 70, 73, 84). HPV-57 was the only type undetected in the cohort. Of 90 men with anoscopy results, 36 were normal, 36 had AIN grade I, and 18 had AIN grade II-III on biopsy. HPV-16 was detected in 12 (33%) of 36 normal men versus 11 (61%) of 18 men with AIN II-III (P=0.05).

All 18 men with high-grade AIN were infected with at least one oncogenic HPV type. A greater number of oncogenic types were identified in specimens from men with high-grade AIN (median of 4, range of 0–9) than normal men (median of 2,5, range of 0–6) (P=0.04, Mann-Whitney).

Norton and colleagues at the Boriken Community Health Centre in East Harlem, New York, recommend routine rectal Pap screening as part of HIV primary care medicine. They say their data support the findings of other groups that have identified a significant prevalence of rectal dysplasia and anal squamous intraepithelial lesions (SIL) among HIV-positive patients, and conclude from the results of their study that the course of rectal disease among HIV-1 infected patients needs additional characterisation. [2]

Their ongoing study of 115 patients, mostly Latino Hispanic subjects and Black/African Americans, found that 70 (69%) were negative for malignant cells.

Thirty-four patients (30%) were found to have some level of rectal dysplasia. In two patients (1.7%) an inadequate sample was reported by pathology. They found the following levels of rectal dysplasia: five patients had high grade lesions and SIL grade III; seven patients had moderate dysplasia and SIL grade II; 12 patients had mild dysplasia and SIL I; and 14 patients had atypical squamous cells of undetermined significance.

References

Unless stated otherwise, references are to the programme and abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003, Paris.

1. Fortin C, Rouleau D, Trépanier JM et al. Anal infection by Human Papillomavirus is universal in HIV-seropositive men. Abstract 941.
2. Norton M, Milano D, Vane C et al. Practicality of and results from rectal Pap smears among patients receiving primary HIV care at a community health centre, NYC, USA. Abstract 945.

Kaposi’s sarcoma (KS) is the most common malignancy experienced in the context of HIV-infection. Although the aetiology and pathogenesis of KS remains ill defined it is known to be an angio-proliferative disease characterised by angiogenesis, endothelial spindle-cell growth, inflammatory cell infiltration and oedema. KS in HIV-infection is also associated with coinfection with human herpesvirus 8 (HHV8), KS development and aggressivity is highly associated with reactivation and viral load of this particular herpesvirus.

Chemotherapy of KS with cytostatic drugs as well as radiotherapy has been found to have variable response rates and has also been associated with an increase in the frequency of opportunistic infections. Recent reports have described both a reduced incidence and regression of KS in HIV-infected patients treated with combination antiretroviral therapy including at least one HIV protease inhibitor (PI). [1] It is unclear, however, if PIs are an essential component of combination antiretrovirals required to bring about such protection or regression of KS. There remains a lack of evidence to conclude if alternative regimens such as those based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) or triple nucleoside analogue (NA) alone offer the same benefits as PIs in terms of KS regression or protection. A single study did, however, identify three patients whose HHV8 viral load and KS showed a reduction after initiation of NNRTI-based regimens. [2]

The KS regression observed with the use of PI based antiretroviral regimens is thought to occur primarily due to the immune reconstitution that occurs after such regimens are initiated. Other studies have indicated that the evolution of AIDS-related KS is greatly dependent on the HIV-1 burden, and the ensuing degree of immunodeficiency. However, both in vitro and animal model studies have also shown that PIs may have a direct anti-KS and/or anti-angiogenic effect that may enhance their potency against KS when used in this setting over and above other classes of antiretroviral agents. Recently Sgadari and colleagues reported data showing that PIs have direct anti-angiogenic, anti-KS and anti-tumour effects. [3]

A report in the journal AIDS by doctors from the Hospital Saint Louis, Paris, appears to be the first publication to identify a relapse of KS in five HIV-infected patients switching from a PI to an NNRTI based antiretroviral regimen. [4] All five patients had experienced widespread KS prior to the use of PI based antiretroviral regimens and had all received treatment with various regimens of cytotoxic chemotherapy and/or radiotherapy. Under PI treatment they had experienced a median duration of complete KS remission of 32 months.

PIs were discontinued due to virological failure in three cases and a wish to simplify therapy in the other two. Substituted therapy consisted of two nucleoside analogues and efavirenz in four patients and two nucleosides and nevirapine in one patient. Overall the median CD4 count did not change significantly after the switch and HIV viral load remained well suppressed. KS relapse was diagnosed within a median of 11 months post-switch and at a median CD4 cell count of 499 cells/mL.

Bani-Sadr and colleagues comment: “Of significance is the fact that the KS relapse was not explained by the immunological or virological failure of NNRTI-based HAART.” They go on to suggest that the relapse may be explained by the antineoplastic effects of PIs, which are independent of their ability to inhibit HIV protease or induce CD4 cell recovery.

A final caution is given that: “A switch from PI to NNRTI should be performed with caution in patients with a history of KS, even though the new regimen is fully active in maintaining HIV viral suppression and high CD4 cell counts.”

References:

1. Cattelan AM, Calabro ML, Aversa SM et al. Regression of AIDS-related Kaposi’s sarcoma following antiretroviral therapy with protease inhibitors: biological correlates of clinical outcome. Eur J Cancer. 1999 Dec;35(13):1809-15.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids=10673996
2. Gill J, Bourboulia D, Wilkinson J et al. Prospective study of the effects of antiretroviral therapy on Kaposi’s sarcoma-associated herpesvirus infection in patients with and without Kaposi’s sarcoma. J Acquir Immune Defic Syndr. 2002 Dec 1;31(4):384-90.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids=12447008
3. Sgadari C, Barillari G, Toschi E et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi’s sarcoma. Nat Med. 2002 Mar;8(3):225-32.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids=11875492
4. Bani-Sadr F, Fournier S, Molina JM. Relapse of Kaposi’s sarcoma in HIV-infected patients switching from a protease inhibitor to a non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy regimen. AIDS. 2003 Jul 4;17(10):1580-1.
   http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids=12824806

The increased risk of developing lung diseases in cigarette smokers has been well recognised. The association between smoking and the risk of developing pulmonary infections in HIV-1-infected patients, however, has not been established.

Researchers from the Department of Psychiatry and Behavioral Sciences at the University of Miami evaluated the effect of tobacco use on respiratory infections in HIV positive patients on HAART. Twenty-seven cases with lower respiratory infections (15 cases of PCP, 12 cases of TB) were compared with the same number of age, gender, socio-economic and HIV status-matched patients, without history of respiratory diseases. Medical history and physical examinations were obtained every six months. Blood was drawn for CD4 and viral load measurements.

A substantial number of HIV-positive smokers who developed PCP (one-third) had been on highly active retroviral therapy (HAART) for more than six months and prophylaxis had been discontinued.

Multivariate analyses indicated that in HIV-infected people, after controlling for HIV status and antiretrovirals, cigarette smoking doubled the risk for developing PCP (p = 0.01). Multivariate analyses demonstrated that long-term smoking also increased the risk (2 x) of developing tuberculosis (p = 0.04).

Moreover, daily tobacco use seemed to attenuate by 40% the immune and virological response to antiretroviral therapies.

These findings indicate that tobacco use significantly increases the risk of pulmonary diseases in HIV-infected subjects and has a potential deleterious impact on antiretroviral treatment.

Ref: Miguez MJ et al. Impact of tobacco use on the development of opportunistic respiratory infections in HIV seropositive patients on antiretroviral therapy. Addict Biol 8(1): 39-43. March 2003.

Source: HIVandHepatits.com

http://www.hivandhepatitis.com/recent/ois/051903f.html

© Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved. Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher. Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (email publisher@HIVandHepatitis.com)

The proportion of HIV-infected patients with high levels of Epstein-Barr virus (EBV) is not affected by highly active antiretroviral therapy (HAART), Dutch investigators report. Thus, clinicians should still test patients for EBV despite the recent decrease in EBV-lymphoma-related morbidity.

In 1999, a research team led by Dr Servi JC Stevens, of the Vrije University Hospital in Amsterdam collected whole blood and parallel plasma samples from 109 patients being treated with HAART. Although all patients had an asymptomatic EBV infection, none developed AIDS-related non-Hodgkin’s lymphoma during follow-up until November of 2001.

The investigators report in the 3 May issue of AIDS that 64 whole-blood samples were polymerase chain reaction (PCR) positive for EBV, and 22 of these had 2,000 or more copies of EBV DNA per mL of blood. However, no cell-free virus was detected in plasma samples. There was no correlation between EBV DNA levels and HIV RNA levels or CD4 counts.

Compared with samples collected between 1993 and 1996 from 99 patients receiving anti-HIV monotherapy, no significant difference in EBV DNA loads was observed. Thus, the authors infer, HAART does not affect EBV burden.

The EBV DNA loads in some HIV-infected individuals “are remarkably higher than those found previously in healthy EBV-seropositive donors, who invariably have <2,000 EBV DNA copies/mL blood,” the investigators note. They suggest that this indicates a partially impaired immune surveillance against EBV in the presence of HIV.

Dr Stevens’ team noted a disparity in IgG responses to EBV VCA-p18 protein and the EBNA-1 protein. In the 14 patients with the highest EBV DNA loads, the anti-VCA-p19 IgG responses were significantly higher than those of patients with undetectable EBV DNA loads (p < 0.0001). However, anti-EBNA-1 IgG responses were significantly lower (p = 0.005). This observation indicates “impaired latency control and increased lytic replication,” the authors write.

Dr Stevens and colleagues suggest that monitoring EBV DNA load and EBV serology may help identify patients at increased risk for lymphomagenesis.

Ref: Stevens SJ, Blank BS, Smits PH et al. High Epstein-Barr virus (EBV) DNA loads in HIV-infected patients: correlation with antiretroviral therapy and quantitative EBV serology. AIDS. 2002 May 3;16(7):993-1001.

Source: HIVandHepatitis.com

http://www.hivandhepatitis.com/recent/malignancies/053003h.html

© Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved. Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher. Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (email publisher@HIVandHepatitis.com)

The objective of the current study was to evaluate higher than recommended doses of oral fluconazole (Diflucan) and itraconazole (Sporanox) as primary therapy for cryptococcal meningitis in AIDS patients.

HIV positive patients with primary cryptococcal meningitis, who had been treated initially with amphotericin B for two weeks were included in this study. They were randomised into two groups: (1) to receive either fluconazole 600 mg daily or (2) to receive itraconazole 600 mg daily for 10 weeks. The response to the two different regimens was defined as successful if after 10 weeks of treatment no clinical symptoms and signs of meningitis remained and the cerebrospinal fluid (CSF) fungal culture was negative.

The trial was performed from April 1999 to April 2000 at Srinagarind Hospital, Khon Kaen, Thailand. Of the 35 patients who proved for the final evaluation of the study, 19 cases were assigned to the fluconazole regimen and 16 to the itraconazole group.

Ten weeks after treatment, all patients recovered completely. The CSF sterilisation rate for the fluconazole group and for the itraconazole group were 100% and 94%, respectively.

The results of this study indicate that treatment with either 600 mg/day of fluconazole or itraconazole as primary treatment have the same efficacy for AIDS patients with cryptococcal meningitis.

According to the study authors: “The results of this study also suggest that treatment with the higher doses (600mg/day vs 200mg/day) may be superior to treatment regimens using lower doses, as can be judged from the clinical outcome and the results of the mycological cultures.”

Source: HIVandHepatitis.com

http://www.hivandhepatitis.com/recent/ois/052803f.html

Ref: P Mootsikapun et al. The efficacy of fluconazole 600 mg/day versus itraconazole 600 mg/day as consolidation therapy of cryptococcal meningitis in AIDS patients. Journal of the Medical Association Thailand 86(4): 293-298. April 2003.

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The landmark study that has defined the current standard of care for cryptococcal meningitis was published by the ACTG and the Mycoses Study group in 1997 (van der Horst C et al. NEJM 1997; 337: 15-21). This established the efficacy of induction therapy with intravenous amphotericin B and flucytosine followed by ten weeks of oral fluconazole (400 mg/day). In that study fluconazole maintenance therapy was superior to itraconazole (400 mg/day) in terms of CSF sterilisation (72% vs. 60%, p=0.05).

This study uses higher doses of maintanence oral fluconazole and itraconazole (600 mg/day), and although the numbers are small, suggests equivalent rates of CSF sterilisation. Itraconazole has poor CSF penetration and an unpredictable oral bioavailability, and careful attention to potential toxicity, drug interactions and serum levels are required. Intravenous induction therapy with amphotericin and flucytosine for the first two weeks is still required.

However, voriconazole, a new azole anti-fingal agent with proven efficacy against invasive aspergilliosis (as compared to amphotericin), has activity against cryptococcal species and good CNS penetration and may be the oral agent of choice in the future.

Rebecca Biggs from St Mary’s Family Clinic, London, highlighted the importance of continual developmental monitoring for HIV positive children in an oral presentation. [1]

This study compared neurological and early developmental outcome of two groups of children under three years and earlier and later disease stages. Group 1 was defined as presenting with severe HIV disease other than encephalopathy (category C) and Group 2 presenting with mild or moderate disease (category A/B).

A paediatric physiotherapist and a paediatrician evaluated the children’s neurological functions, and development was assessed using the Bayley Scales of Infant Development II by a clinical psychologist and paediatric physiotherapist.

The investigators found 43% of children in group 1 (n=32, mean age at assessment 16 months) had abnormal neurological signs compared to 7% (n=31, mean age 18 months) in group 2. Twenty per cent of group 1 and 61% of group 2 had developmental scores within the normal range in both mental and motor functions.

The investigators concluded that in the era of HAART severe early HIV disease still relates to abnormal neurology with motor impairment and developmental delays, and that children are surviving longer with developmental needs. They stressed the need for regular developmental monitoring and these results have implications for community services.

Transition from paediatric to adult care

A poster from Dr K Miles and colleagues from Mortimer Market explored the (complicated and very much on the upswing) issue of HIV positive adolescents in transition from paediatric to adult care. [2]

This small study reports findings from semi-structured interviews with seven adolescents who have undergone transition from paediatric to adult HIV outpatient services.

Issues concerning stigma, new sexual opportunities and the loss of a lifetime healthcare team are all difficult factors for adolescents transferring care from paediatric to adult clinics. The investigators emphasised that “Neither a simple transfer to adult services nor allowing adolescents to ‘drop out’ of medical care is considered acceptable care for young people with HIV”.

The feedback from those interviewed include a beneficial effect of including adult healthcare providers early on in the preparation for transition, concerns over the co-ordination of haemophiliac and HIV care (anecdotally this seems complex throughout adult care), and lack of preparedness for an adult and predominately gay clinic population. The benefits included a sense of independence, increased responsibility and the satisfaction of being treated as an adult. Those who had had a strong rapport with their paediatric HIV team experienced a sense of loss. Some found the transition ‘easy’ and others expressed concerns.

The investigators felt that this study supports the need for effective transition protocols and the development of adolescent-specific models of care to best facilitate this crossover from paediatric to adult care facilities and their ongoing care as adults.

References:

All references are to abstracts presented at 9th BHIVA Conference, 24-26 April 2003, Manchester.

1. Lyall EGH, Foster C, Melvin D et al. Neurological and developmental outcomes in HIV-infected children presenting before 3 years of age. Abstract O5
2. Miles K, Prime K, Sudlow J et al. Bridging the gap between paediatric and adult HIV services. Abstract P21

Oxymetholone, an anabolic steroid, appears to be effective in countering wasting among HIV-positive patients taking highly active antiretroviral therapy (HAART).

This finding results from a double-blind, randomised, placebo-controlled trial at the University of Essen, and the University of Bonn, Germany. Eighty-nine HIV-positive women and men participated.

Chronic involuntary weight loss is a serious problem among patients on HAART. The alterations in energy metabolism and endocrine regulation cause loss of lean body mass (LBM) and body cell mass (BCM).

There has been partial restoration of LBM in studies among HIV-positive men undergoing androgen replacement therapy, or treatment with recombinant growth hormone. However, these treatments have largely been ineffective among eugonadal individuals.

In the present study, the men and women with wasting were given oxymetholone 50 mg twice (BID), or three times daily (TID), or placebo for 16 weeks, followed by open-label treatment. Endpoints were body weight, bioimpedance measurements, and appetite.

The clinicians found that oxymetholone produced a significant weight gain of 3.0 ± 0.5 kg in the TID group, and 3.5 ± 0.7 kg in the BID group, while patients in the placebo group gained an average of 1.0 ± 0.7 kg. Body cell mass increased 3.8 ± 0.4 kg in the BID group and 2.1 ± 0.6 kg in the TID group. This corresponded to 12.4T and 7.4% of baseline BCM, respectively.

The patients taking oxymetholone reported significant improvements in their appetite and food consumption, plus a reduction in feeling weak. The most important adverse event was liver-associated toxicity.

Overall, 35% of patients in the TID, 27% of patients in the BID oxymetholone group, and no patients in the placebo group, had a greater than five times baseline increase for alanine aminotransferase during the double-blind phase of the study.

Clinicians concluded that “the BID (100 mg/day) regimen appeared to be equally effective as the TID (150 mg/day) regimen in terms of weight gain, LBM and BCM and was associated with less, but still significant liver toxicity.”

Source: Doctors Guide Review. April 1, 2003.

Ref: Hengge UR, Stocks K, Wiehler H et al “Double-blind, randomized, placebo-controlled phase III trial of oxymetholone for the treatment of HIV wasting.” AIDS 2003 Mar 28; 17:5:699-710.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12646793&dopt=Abstract

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Anabolic steroids have however been proven to be ineffective in lipoatrophy and may worsen lipid profiles considerably (HDL decrease, LDL increase).

In addition pharmacologic application of anabolic steroids suppress the bodies natural production testosterone.

US researchers found that functional magnetic resonance imaging (fMRI) can offer early warning of neurologic morbidity in HIV patients. “A previous fMRI study demonstrated increased brain activation during working memory tasks in patients with HIV with mild dementia,” wrote Thomas Ernst and colleagues at Brookhaven National Laboratory in Upton, NY, the Massachusetts Institute of Technology- Cambridge and the University of California-Los Angeles Medical Center in Torrance.

Ernst and colleagues discovered that fMRI screening could detect neurologic abnormalities even in patients who have no overt symptoms of dementia. The researchers evaluated the utility of blood oxygenation level-dependent fMRI for finding abnormal brain activity. A group of 10 HIV patients with low CD4 cell counts underwent neuropsychological tests under fMRI. The investigators compared their results with those of age-, sex-, education-, and handedness-matched seronegative controls, according to the study.

Although the HIV patients did not suffer from impaired test performance, fMRI showed significant increases in their lateral prefrontal cortex activation and activated brain volume, data revealed. The asymptomatic patients showed heightened activated brain volume in the lateral prefrontal cortex during all of the assigned tasks, regardless of the difficulty. The investigators found that fMRI measurements of brain activity and activated volume were similar in other regions of the brain between patients and controls.

“Increased brain activation in subjects who are positive for HIV precedes clinical signs or deficits on cognitive tests,” Ernst and colleagues concluded. “ fMRI appears to be more sensitive than clinical and neuropsychological evaluations for detecting early HIV-associated brain injury.”

Ref: Ernst T, Chang L, Jovicich J et al. Abnormal Brain Activation on Functional MRI in Cognitively Asymptomatic HIV Patients” in Neurology (2002;59(9):1343-1349).
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12427881&dopt=Abstract

Source: CDC NCHSTP Daily Summaries
http://www.aegis.com/todaysnews/du.asp#3810

Highly active antiretroviral therapy (HAART) has significantly improved outcomes in HIV-infected patients. In some patients, however, the initial few months of HAART may be complicated by immune restoration disease (IRD), also known as immune reconstitution disorder In most patients who encounter IRD it is related to cytomegalovirus or nontuberculous mycobacteria (most notably, mycobacterium avium complex), but there have been reports of other opportunistic pathogens also being associated with IRD. While most cases of IRD that have been reported resolved spontaneously with continuation of HAART and, in some cases, treatment of the pathogen, there is a potential risk for severe morbidity and mortality in these patients.

In a report published in Clinical Infectious Diseases, two cases of progressive multifocal leukoencephalopathy (PML)-associated IRD were presented. This report is notable in that while in most HAART-treated patients PML improves as the patient’s immune function does, these two patients had a significant and “paradoxical” worsening after the commencement of HAART. Both of these patients, despite a transient response to high-dose corticosteroid therapy, subsequently died of progressive neurological deterioration.

In evaluating these two cases, the authors state: “IRD in these patients with PML was unexpected and occurred soon after they had started receiving active antiretroviral therapy, during the period of improved antigen-specific T-helper cell function. Predictors of patients’ proclivity for these adverse events are uncertain. Evaluation of targeted immunomodulatory therapy directed towards disease-specific IRD is critical and may play an important role in improved survival for patients who are at risk.”

These cases emphasise the importance of carefully monitoring patients starting HAART, especially those with low CD4+ T cell counts or a history of an opportunistic infection at HAART initiation, and also indicate the need for further research into methods for blunting or avoiding the severe IRD that may occur in some patients. Finally, this is yet another reason why starting therapy earlier rather than later may be important in avoiding morbidity and mortality associated with HIV and its complications.

Ref:
Safdar A, Rubocki RJ, Horvath JA et al. Fatal immune restoration disease in HIV-1 infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002 Nov 15;35(10):1250-7

“Helminthic infection affects a huge number of people in the world, and plays a very important role in making them more susceptible to HIV and tuberculosis and less able to mount a proper immune response. Thus, eradication of helminths may change the face of the AIDS and tuberculosis epidemics,” said Dr Zvi Bentwich.

Dr Bentwich, from Hebrew University Hadassah Medical School in Rehovot, Israel, and colleagues investigated whether treatment of helminthic infections would affect HIV disease progression in 56 otherwise asymptomatic HIV-positive Ethiopian patients – for whom antiretroviral treatment is unavailable and in whom helminthic infections are common.

Among the 31 patients with helminthic infections at baseline, there was a strong association between the helminthic load (as measured by the amount of eggs excreted in stools) and the HIV plasma viral load, the authors report.

Antihelminthic treatment clearly reduced the proportion of helminth-infected patients and the helminthic load in patients infected at baseline. According to the report, the successful treatment of helminthic infection was associated with a significant decrease in HIV levels, while the group of patients whose helminthic infections were not eradicated experienced a significant increase in mean HIV load.

“The decrease in HIV viral load, even of 0.35 logs only, is expected to have a very significant impact on the spread of the epidemic in the developing countries,” Dr Bentwich commented.

CD4+ T-lymphocyte counts did not change significantly during the course of the six-month study, the results indicate.

“In the absence of antiretroviral therapy in Africa, and the serious problems of compliance to ART even if it was available, eradication of helminths is a very attractive, simple, cheap and feasible measure to curb HIV infection,” Dr. Bentwich concluded.

Ref: Wolday D, Mayaan S, Mariam ZG et al. Treatment of Intestinal Worms Is Associated With Decreased HIV Plasma Viral Load. J Acquir Immune Defic Syndr 2002 Sep 1;31(1):56-62

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12352151

Source:

Reuters Health

Few treatment options exist for patients with advanced AIDS-KS whose disease has progressed after receiving therapy with liposomal anthracyclines or combination chemotherapy, study author Dr. Parkash S. Gill, from the University of Southern California at Los Angeles, and colleagues note.

Dr. Gill’s team evaluated the safety and efficacy of paclitaxel in 107 male patients with advanced AIDS-KS who had failed at least one previous systemic chemotherapy regimen. The drug was given intravenously at a dose of 100 mg/m” over three hours, every two weeks.

Fifty-six percent of patients experienced a complete or partial response and the median duration of response was nearly nine months, the authors note. Almost half of the patients were taking a protease inhibitor at study entry, but the use of such agents had no bearing on the likelihood of achieving a response. Still, survival tended to be better when a protease inhibitor was used (p = 0.08).

In general, life-threatening side effects were uncommon. However, 35% of patients did experience life-threatening neutropenia and two patients died of associated sepsis, the researchers point out.

Treatment with paclitaxel was associated with a significant improvement in overall quality-of-life scores as well as improvements in KS-related symptom scores.

The present results indicate that “paclitaxel is a very active drug for this disease,” Dr. Gill told Reuters Health. “The FDA’s approval of paclitaxel for KS was actually based on data from the current study,” he added.

“Another drug that has been shown to be effective for AIDS-KS is pegylated liposomal doxorubicin (Doxil),” Dr. Gill noted. “Currently, there is a head-to-head study underway comparing paclitaxel with Doxil,” he said.

Ref: Cancer 2002; 95:147-154.

Source: Reuters Health

Prior to the advent of highly active antiretroviral therapy (HAART), neutropenia was a relatively common finding in patients with AIDS, study author Dr Douglas A Jabs, from the Johns Hopkins University in Baltimore, and colleagues note in the March 29th issue of AIDS

Because neutropenia is an established risk factor for bacterial infection, the authors hypothesised that treatment with filgrastim — granulocyte colony-stimulating factor, which reverses neutropenia — might prevent such infections and thereby improve survival.

To investigate, the researchers retrospectively studied 709 patients with AIDS-related CMV retinitis who were treated between 1990 and 1997. Of these patients, 398 had used filgrastim at some point.

Filgrastim use was associated with a significant reduction in the risks of catheter-related bacteremia and repeat bacterial infection (p = 0.02 and < 0.01, respectively), Dr Jabs and colleagues found.

However, after adjustment for CD4+ T-cell count and antibiotic/antiretroviral therapy, filgrastim therapy was no longer linked to a significant reduction in these risks. The authors believe this may have been due to the confounding effect of trimethoprim-sulfamethoxazole use.

Despite no clear effect on bacterial infections, filgrastim use was tied to a 56% reduction in mortality (p < 0.001), the researchers state.

“Our observation of a large survival benefit with the use of filgrastim, while unexplained by a reversal of neutropenia or reduction of infection, deserves further exploration in a randomised controlled trial of this cytokine in non-neutropenic AIDS patients receiving HAART,” Dr Jab’s team concludes.

COMMENT

Similar benefits in advanced disease have also been reported for the immunotherapy agents GM-CSF (molgramostim) and gamma interferon.

Upregulation of phagocytic responses to pathogens may be one mechanism of action as well as improved antigen presentation and perhaps increased IL-2 receptor expression.

Ref: Davidson M, Min YI, Holbrook JT et al. Use of filgrastim as adjuvant therapy in patients with AIDS-related cytomegalovirus retinitis. AIDS 2002 Mar 29;16(5):757-65

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11964532&dopt=Abstract.

Source: Reuters Health

Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long term management of cytomegalovirus (CMV) retinitis in patients with AIDS, according to the results of a randomised trial reported in the 11 April issue of the New England Journal of Medicine.

Dr Daniel F Martin and colleagues at the Valganciclovir Study Group write: “The results of our study indicate that a twice-daily dose of 900mg of oral valganciclovir for induction therapy in patients with cytomegalovirus retinitis has an efficacy and safety profile that is similar to the profile for intravenous ganciclovir. The proportions of patients with progression of retinitis during the first four weeks were similar for the two regimens.”

CMV retinitis remains the leading cause of loss of sight in people with AIDS. Induction therapy with ganciclovir, foscarnet or cidofovir, followed by maintenance therapy can effectively make CMV retinitis inactive. If recovery of immune function is not possible, indefinite treatment is needed, and an indwelling catheter to facilitate regular intravenous medication may be required. The cost, risk of sepsis, and effect on quality of life of having a permanent indwelling catheter provoked the search for an orally administered treatment.

Valganciclovir is an orally administered prodrug that is rapidly hydrolysed to ganciclovir. Dr Martin’s team compared the effects of oral valganciclovir with those of intravenous ganciclovir as induction therapy for newly diagnosed CMV retinitis in 160 patients with AIDS.

Eighty patients were randomly assigned to each treatment group. Of the patients who could be evaluated, seven of 70 assigned to intravenous ganciclovir (10.0%) and seven of 71 assigned to oral valganciclovir (9.9%) had progression to CMV retinitis during the first four weeks.

Forty-seven of 61 patients (77.0%) assigned to intravenous ganciclovir, and 46 of 64 (71.9%) assigned to valganciclovir had a satisfactory response to induction therapy.

The median times to progression of retinitis were 125 days in the group assigned to intravenous ganciclovir and 160 days in the group assigned to oral valganciclovir.

The researchers also report that: “The frequency and severity of adverse events were similar in the two treatment groups.” They go on to say that the main difference in safety between the two treatments was related to the mode of administration, with more diarrhoea in the oral valganciclovir group and more catheter-related complications in the intravenous group.

The study was not designed to evaluate the differences between the treatments for maintenance therapy, and the team say this would require a randomised comparison of patients followed up to the time of the progression of retinitis. However, they add: “On the basis of its efficacy for induction, and the pharmacokinetic data, we would expect valganciclovir to compare favourably with both intravenous and oral ganciclovir for maintenance therapy.”

They write that the reduced pill burden and once daily dosing with oral valganciclovir for maintenance treatment may increase adherence and therefore improve outcomes.

In their discussion, the researchers also comment: “Although there is no evidence on the basis of HIV loads and CD4+ cell counts, that highly active antiretroviral therapy affected our primary outcome at four weeks, it almost certainly influenced the observed times to progression of retinitis.”

The researchers end their discussion by advising: “Because of the heterogeneity of the immune response to highly active antiretroviral therapy, the time to the progression of retinitis may vary widely from patient to patient. Careful surveillance for progression of retinitis is therefore recommended throughout treatment.”

COMMENT

Well designed prophylaxis studies are now urgently needed to determine if oral valganciclovir is an effective agent for prevention as well as treatment of CMV retinitis.

Ref: Martin D. F., Sierra-Madero J., Walmsley S et al. A Controlled Trial of Valganciclovir as Induction Therapy for Cytomegalovirus Retinitis. N Engl J Med 2002; 346:1119-1126, Apr 11, 2002.

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The development and recurrence of cervical lesions associated with the human papillomavirus (HPV) are more common in HIV-infected women than in HIV negative women, according to an Italian study of 1,336 patients.

Relapses after treatment for external genital warts were more common in women with HIV than in those without, report Dr Giuseppe De Panfilis and colleagues at the Department of Dermatology at Brescia Hospital, Brescia, Italy, in the March issue of the journal Sexually Transmitted Diseases. They advise clinicians to encourage patients with recurring genital warts to be tested for HIV.

Dr De Panfilis and colleagues compared relapses after treatment for external genital warts in 241 HIV-positive and 1,095 HIV-negative patients examined between 1990 and 1999 at the STD centre at Brescia. Various local treatments were used.

Treatment generally triggered recovery from the lesions, report the researchers, but the relapses observed up to one year after response, examined by survival analysis, were significantly (P < 0.001) more frequent in the HIV-positive (160 cases, 66.4%) than in the HIV-negative (294 cases, 26.8%) subjects. Multiple relapses observed up to one year after treatment occurred in 69 of 241 HIV-positive patients, as compared with 14 of 1,095 HIV-negative subjects (P < 0.001).

A comparable pattern of recurrences of cervical intraepithelial neoplasia (CIN), which like genital warts are also associated with HPV, was also observed by Dr De Panfilis and colleagues. In 127 HIV-positive women referred for CIN evolution, recurrences continued to develop after treatment, reaching 62% by three years. However, CIN recurred in only 18% of 193 HIV-negative patients over a similar time period.

The authors write: “Thus, as with CIN, we can assume that the natural histories of external genital warts after treatment in HIV-positive and HIV-negative subjects are distinct.”

And they conclude: “According to the study findings, HIV infection can be considered a risk factor for the development and recurrence of external genital warts. Multiple relapses should drive patients to HIV testing.”

Ref : De Panfilis G, Melzani G, Mori G et al. Relapses after treatment of external genital warts are more frequent in HIV-positive patients than in HIV-negative controls. Sex Transm Dis 2002 Mar;29(3):121-5

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Infection with Kaposi’s sarcoma-associated herpesvirus (KSHV) is common among men who have sex with men (MSM), according to a study by researchers in Seattle, USA.

The incidence of KSHV among the gay and bisexual men studied is even higher than the incidence of genital herpes, the researchers report in the 1 April issue of the Journal of Infectious Diseases.

The study, aimed at determining the correlates of infection, assessed 578 HIV-negative MSM by serologic assays, questionnaires, and physical examinations. Of those, 474 were studied for 12 months. At baseline 76 (16%) were KSHV seropositive.

The researchers from the University of Washington Department of Medicine did not find any sexual behaviour particularly associated with having antibodies to KSHV, but multivariate analysis revealed that a history of hepatitis A, serology suggesting hepatitis B or HSV-2 infection, and a history of more than four sex partners in the previous six months were all independent predictors.

The researchers, led by Dr Corey Casper, report that prevalent KSHV infection was significantly associated with hepatitis A (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.5-7.5), hepatitis B seropositivity (OR, 2.6; 95% CI, 1.4-4.8), herpes simplex virus (HSV)-2 (OR, 2.4; 95% CI, 1.3-4.4), and more than four male partners in the previous six months (OR, 1.9; 95% CI, 1.1-3.2).

Fifteen KSHV seroconversions (4%) were observed for an incidence of 3.8/100 person-years, similar to HSV-1 incidence in this cohort and more frequent than incidence of HIV and HSV-2.

Reporting >/=1 HIV-positive partner (OR, 5.9; 95% CI, 1.8-19.3), amyl nitrite use (OR, 7.0; 95% CI, 2.1-23.0), and lymphadenopathy in the past six months (OR, 7.7; 95% CI, 1.9-31.0) correlated with KSHV seroconversion.

Dr Casper says the study is the largest prospective study looking at incident infection but still there were only 15 men who had new infections. He said the fact that there wasn’t statistical significance did not mean there wasn’t an association.

The researchers believe the virus may be transmitted through saliva and in a large study of almost 1,000 participants they are starting to ask questions not only relating to whether or not the participants have anal, oral, protected and unprotected sex but also questions about the exchange of saliva.

Ref: Casper C, Wald A, Pauk J et al. Correlates of Prevalent and Incident Kaposi’s Sarcoma-Associated Herpesvirus Infection in Men Who Have Sex with Men. J Infect Dis 2002 Apr 1;185(7):990-3

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In a study of 259 HIV-infected drug users assigned to receive placebo or selenium supplements 200 µg/day, Dr. Gail Shor-Posner and colleagues, of the University of Miami School of Medicine, identified 12 subjects who developed infections of Mycobacterium tuberculosis or atypical mycobacterial species during a two year follow up. They were compared with 32 matched controls.

All subjects had plasma selenium levels considered to be normal, but those with levels of 135 µg/L or less were 13 times more likely to develop mycobacterial disease, the investigators report in the Journal of Acquired Immune Deficiency Syndromes for February 1. Furthermore, receiving placebo rather than selenium supplements doubled the risk.

Dr. Shor-Posner’s group notes that selenium is recognized as a suppressor of tumour necrosis factor-alpha and an aid in maintaining T cell function. The researchers also suggest that selenium modulates viral expression and acts as an antioxidant. Thus, “higher than normal levels of selenium may be necessary to maintain a functional immune system in HIV-infected subjects,” they maintain.

Ref: J Acquir Immune Defic Syndr 2002; 29:169-173.

Source: Reuters Health

Highly active antiretroviral therapy containing protease inhibitors (PIs) have an early beneficial effect on Candida virulence in the oral cavities, independent of any immune reconstitution, report Italian researchers.

Dr Antonio Cassone and colleagues at the department of Bacteriology and Medical Mycology of the Instituto Superiore di Sanita in Rome, say that PIs have this beneficial effect within weeks of starting treatment.

Previously Dr Cassone and colleagues had reported that some patients treated with PIs showed resolution of oral candidiasis long before any rise in the CD4+ T cell counts. The researchers hypothesised that PIs inhibited the activity of secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. In the January 15 issue of the Journal of Infectious Diseases they report confirmation of this effect in a cross-sectional study of 30 therapy-naïve patients with HIV.

One group of 15 patients was treated with PI containing HAART regimens, and another group of 15 patients was treated with NNRTI HAART. The researchers tested saliva samples from all subjects on days 0, 14, 30, 90 and 180.

Of those treated with PI HAART, Sap was detected in the saliva of 11 patients at baseline and then in 6, 3, 0 and 0 at subsequent points. Of those treated with NNRTI HAART, Sap was detected in 7 patients at baseline and then in 7, 9, 6, and 5 patients at subsequent points.

In another 30 patients Sap was detected in 0 of 15 after one year on PI HAART, and it was detected in 7 of 15 subjects after a year of treatment on NNRTI HAART.

Dr Cassone and colleagues write: “The anti-Sap effect of PI HAART was associated with clinical resolution of oral candidiasis but not with late and inconstant recovery of anticandidal cellular immunity.

“In all subjects the two therapeutic regimens compared well in increasing CD4+ T cell counts and abating viraemia. Thus, PIs exert an early, immune reconstitution-independent effect on candida virulence in the oral cavities of HIV-positive subjects.”

Ref: J Infect Dis 2002;185:188-195.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11807692&dopt=Abstract

The major European study project, EuroSIDA, has published further evidence that there has been a significant decrease in the incidence of non-Hodgkin lymphomas (NHL) in people with HIV since the widespread use of highly active antiretroviral therapy (HAART).

The new evidence is published by Dr Ole Kirk and colleagues at the EuroSIDA Coordinating Centre at Hvidovre Hospital, Copenhagen, who studied the impact of HAART on NHL within EuroSIDA’s multicentre observational cohort of more than 8,500 patients across Europe. They studied the incidences of NHL and subtypes including Burkitt, immunoblastic, primary brain lymphoma (PBL) and lymphomas of other or unknown histology in people on combinations of three or more antiretrovirals, who they followed from May 1994 to the end of 2000.

The researchers found that the incidence of NHL in the cohort fell 6-fold following the introduction of HAART. Over 26,764 person-years of prospective follow-up (PYF) the incidence of NHL decreased from 1.99 before September 1995 to 0.30 cases per 100 PYF after March 1999. The incidence of all subtypes of NHL decreased significantly, but most pronouncedly for primary brain lymphoma, the researchers report in the 1 December issue of the journal Blood. They write that the latest CD4 T cell count and plasma viral load were both significantly associated with diagnosis of NHL.

They conclude: “The Incidence of NHL among HIV-infected patients has decreased significantly after the introduction of HAART, and the decline was most pronounced for PBL. After starting HAART, patients with insufficient immunologic and virologic response were at highest risk of NHL.”

Reference: Kirk O, Pedersen C, Cozzi-Lepri A et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001 Dec 1;98(12):3406-12.

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A study of the French Hospital Database on HIV that compares the incidence and risk factors for toxoplasmic encephalitis before and after the widespread introduction of highly active antiretroviral therapy (HAART) concludes that HAART and immune recovery help protect people from HIV-related toxoplasmosis.

The protection provided by cotrimoxazole against toxoplasmic encephalitis (TE) is greater when HAART boosts the patient’s CD4+ T cell count, report Dr Sophie Abgrall and colleagues at L’Institut National de la Santé et de la Recherche Médicale at Paris, France. And they go on to say, in the 15 November issue of the journal Clinical Infectious Diseases, that in some patients prophylaxis with cotrimoxazole can be safely discontinued.

The researchers studied the occurrence of TE in 19,598 positive people between 1992 and 1995, before the use of HAART, and compared them with 17,016 positive people between 1996 and 1998, after the introduction of HAART. All those studied had CD4+ T cell counts of 200 or fewer cells/mm3. They found that the incidence of TE decreased from 3.9 cases per 100 person years in the first period, to 1.0 cases per 100 person years in the second period.

After adjustment for know risk factors for TE, patients who received cotrimoxazole prophylaxis had a lower risk of TE – down by 36 per cent in the period before HAART, and by 46 per cent in the period after HAART was introduced. For patients treated with cotrimoxazole at inclusion, discontinuation of cotrimoxazole increased the risk of TE in both periods.

The risk of TE was significantly increased in patients with CD4+ T cell counts below 100 cells/mm3 and in patients with higher levels of plasma HIV RNA. Among patients whose CD4+ T cell counts increased to greater that 200 cells/mm3 while taking HAART, the incidence of TE was 0.1 cases per 100 person years and was not increased by the discontinuation of cotrimoxazole.

The researchers conclude: “This prospective cohort study further supports the efficacy of cotrimoxazole prophylaxis in protection against toxoplasmic encephalitis, with a further protective effect of HAART and immune recovery, and a deleterious effect of cotrimoxazole discontinuation in immunodeficient patients.”

“Prophylaxis against toxoplasmosis and potent antiretroviral therapies are still necessary for strongly immunodeficient HIV-infected patients when immunosuppression progresses,” they write, adding that “discontinuation of cotrimoxazole prophylaxis seems feasible for patients who have a sustained increase in the CD4 cell count to more than 200 million cells/L during HAART.”

Ref: Abgrall S, Rabaud C and Costagliola D. Incidence and risk factors for toxoplasmic encephalitis in human immunodeficiency virus-infected patients before and during the highly active antiretroviral therapy era. Clin Infect Dis 2001 Nov 15;33(10):1747-55.

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“In part because KS was so rare in the US prior to the HIV epidemic, it had been assumed that KSHV infection was also rare before the HIV epidemic. However, we found a high percentage — about one in four — of gay men infected with KSHV before large numbers were infected with HIV,” said the study’s lead author, Dennis Osmond PhD, associate professor in the UCSF department of epidemiology and biostatistics.

“Furthermore, we found that the level of KSHV infection in gay men was remarkably unchanged from 1978 to 1995. This suggests that any prior reports of a decline in KS before the era of highly active antiretroviral therapy (HAART) are not explained by a decline in transmission of KSHV. In fact, when we re-examined available data for a decline in KS, we were unable to confirm the prior reports,” said Osmond.

“We also found a significant decrease in the practice of unprotected anal intercourse among gay men in San Francisco between 1984 and 1995. This likely explains the decline in HIV transmission observed among gay men during this time. However, the frequency of oral intercourse did not change. Because the prevalence of KSHV infection did not change during this time, this suggests that oral intercourse is a more likely route of KSHV transmission than anal intercourse.

Since KSHV is much more commonly present in saliva than in semen, this suggests that the practice of insertive penile-oral intercourse might be most important in the transmission of KSHV,” said Jeffrey N. Martin MD MPH, assistant professor in the UCSF department of epidemiology and biostatistics, who directed the study with Dr Osmond.

The study, published in the 9 January issue of the Journal of the American Medical Association, examined stored serum from three earlier studies of gay men in San Francisco in 1978-80, 1984-85, and 1995-96. The San Francisco City Clinic Cohort, the first study, screened 6,709 gay men between 1978 and 1980. Testing of the serum samples collected in the first six months of 1978 showed 24.9% infected with KSHV and only 1.8% infected with HIV.

The percentage of gay men infected with HIV rocketed to 50% while the percentage infected with KSHV was steady at 29.6% in the second study. The San Francisco Men’s Health Study was a population based probability sample of gay men with the serum specimens drawn in 1984 and 1985. In this study, 54% of gay men reported unprotected penile-anal intercourse with one or more partners. The rate of unprotected penile-oral intercourse was just over 60%.

The last study was also a population based probability sample of gay men. The San Francisco Young Men’s Health Study collected serum specimens in 1995-96. The rate of HIV infection dropped to 18% while the rate of KSHV infection was stable at 26.4%. At this time, only 11% of gay men reported unprotected receptive penile-anal intercourse. However, the rate of unprotected penile-oral intercourse remained high, over 80%.

Ref: Osmond DH, Buchbinder S, Cheng A et al. Prevalence of Kaposi’s Sarcoma-Associated Herpesvirus Infection in Homosexual Men at Beginning of and During the HIV Epidemic. JAMA 2002 Jan 9;287(2):221-5.

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Source: UCSF News

Anaemia is common in HIV infection, and the likelihood of anaemia increases significantly as the patient progresses from asymptomatic HIV infection to immunologic and clinical AIDS.

In prior studies involving HIV-infected patients, anaemia has been found to correlate with the patients’ overall quality of life and to be independently associated with increased morbidity and mortality. Generally, the correction of anaemia leads to improved quality of life and decreases in morbidity and mortality in HIV-infected patients. Thus, monitoring HIV-infected patients for anaemia and, when found, the institution of appropriate treatment may have a significant impact upon the overall health and quality of life of HIV-infected patients.

In order to determine how highly active antiretroviral therapy (HAART) and other factors affected anaemia in HIV-infected patients, researchers at Johns Hopkins analysed data from 905 patients who received HIV care at that centre after 1 July, 1996. Analyses were done of haemoglobin levels obtained at baseline and during one year of follow-up in patients who received and did not receive a HAART regimen.

The researchers found that at baseline 11% of patients had a haemoglobin count <10 g/dL, 27% had a haemoglobin count 10 to 12 g/dL, and 21% had a haemoglobin count of >14 g/dL at baseline before HAART was started. During one year of follow-up, 42% of the patients on HAART achieved a haemoglobin level >14 g/dL. In contrast, only 31% of patients who did not use HAART achieved that haemoglobin level.

The use of zidovudine (ZDV) in the HAART regimen did not appear to have an impact upon the overall effectiveness of HAART in improving anaemia outcomes. Using a multivariate analysis, after adjustment for gender, race, injection drug use history, baseline CD4 and HIV-1 RNA levels, and anaemia treatments, the use of HAART was strongly associated with not having anaemia during one year of follow-up.

Based upon these findings, the authors conclude, in line with prior studies, “HAART is an effective treatment of the anaemia of HIV infection.” While other studies have indicated that patients on HAART regimens that include ZDV do not achieve haemoglobin levels comparable to those on HAART regimens that do not contain ZDV, this study failed to find that ZDV had a significant impact upon haemoglobin recovery.

Still, clinicians confronted with an anaemic, HIV-infected patient should design a HAART regimen most likely to lead to improved haemoglobins, and given its known impact upon haemoglobin – especially in patients with AIDS – consideration should be given to AZT-sparing regimens, if that option exists. Further, a thorough anaemia workup and adjunctive therapy, where appropriate, should also be considered.

Ref: Moore RD, Forney D. Brief Report: Anaemia in HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy. J Acquir Immune Defic Syndr 2002 Jan 1;29(1):54-7.

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Dr Emmett T Cunningham Jr, of the University of California at San Francisco and a multicentre team reviewed the cases of five AIDS patients with ischemic maculopathy in an attempt to gain a greater understanding of this “uncommon disorder.” There are “few” cases of HIV-related symptomatic ischemic maculopathy in the medical literature, they write.

In all five cases, fluorescein angiography facilitated the diagnosis of ischemic maculopathy following complaints of vision loss. Onset was usually abrupt with “opacification of the superficial retina, resulting in a cherry red spot, and intraretinal haemorrhages near the fovea” clearly present in most, but not all cases. Because these changes may be absent or transient in some patients, the researchers recommend that fluorescein angiography be performed in all HIV-infected patients with unexplained vision loss.

Four of the five patients had bilateral macular disease and visual acuity at presentation varied widely, ranging from “20/20 to counting fingers,” Dr Cunningham’s team reports.

The pathogenesis of ischemic maculopathy remains unknown, although the evidence in this case series points to occult herpetic infection as a contributing factor, they write. Seven affected eyes had cytomegalovirus (CMV) retinitis and all patients were taking anti-CMV agents when they developed visual problems.

“HIV infection itself is capable of reducing vision by damaging the fine capillaries of… the macula,” Dr Cunningham said. “This cause of vision loss might be easily missed if not looked for specifically with fluorescein angiography.”

COMMENT

Ischemic maculopathy is caused by blockage of tiny blood vessels in the macula and has been reported as leading to vision loss in HIV-infected patients in the UK and only occurs in people who have had CMV retinitis. It may well be a late finding after cystoid macula oedema associated with severe immune recovery uveitis that has not been treated aggressively when first seen or that is unresponsive to treatment.

Flourescein is an inexpensive, non-toxic, highly fluorescent compound. It absorbs blue light and emits yellow-green light, and therefore only relatively simple modification of existing fundas cameras is necessary to perform angiography.

Fundus photography in rapid sequence after intravenous injection of fluorescent dye provides information on the flow characteristics in the blood vessels, and fine details of the retina and choroids that may not be appreciated by other means. Normal retinal vessels are impermeable to the dye. This allows a clear picture of the retinal vessels and assessment of their functional integrity, since leakage from any retinal vessel is abnormal.

The advice from Dr Cunningham, one of the most experienced doctors in this field, should be adopted for all patients in this situation.

Ref: Cunningham ET Jr, Levinson RD, Jampol LM et al. Ischemic maculopathy in patients with acquired immunodeficiency syndrome. Am J Ophthalmol 2001 Nov;132(5):727-33.

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Source: Reuters Health

The incidence of systemic and primary brain AIDS-related lymphoma (ARL) has reduced since the introduction of HAART, French investigators report. They also find that prognosis of ARL has improved during this time.

Dr Caroline Besson of Hôpital Necker in Paris and colleagues at sites around France report the findings in the October 15 issue of Blood. They note that while the use of HAART has led to a decrease in the incidence of AIDS-defining illnesses, the consequences of HAART on ARL are -under debate. -

This study compared the incidence and characteristics of ARL before and after the use of HAART in a large population of HIV infected patients recorded in the French Hospital Database on HIV, including 145 patients with proven lymphoma. They compared the periods 1993-4 and 1997-8.

The researchers found that the incidence of systemic ARL decreased during that time from 86.0 per 10,000 person-years to 42.9 per 10,000 person-years. The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10,000 to 9.7 per 10,000 person-years.

Another analysis shows known HIV history was longer in the second period than in the first among patients with systemic ARL (98 versus 75 months). Patients had higher CD4 counts at diagnosis during the second period (191 versus 63µL). Survival of patients with systemic ARL increased between the periods from 6 to 20 months.

- Therefore, – the researchers conclude, -the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved. -

Ref: Besson C, Goubar A, Gabarre J, Rozenbaum W et al. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001;98:2339-2344.

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Ref: Moulignier A et al. Reversible ALS-like disorder in HIV infection. Neurology 2001 Sep 25;57(6):995-1001

The sensory neuropathy that affects as many as 35% of AIDS patients predominantly affects small-fibre sensory nerves, the activity of which is modulated to some degree by NGF, the authors explain.

Dr. Giovanni Schifitto, from the University of Rochester, New York, and colleagues studied the safety and effectiveness of recombinant human NGF for HIV-associated distal sensory polyneuropathy in 200 affected subjects.

Pain scores improved consistently in all patient groups (that is, patients receiving either 0.1 µg NGF per kg or 0.3 µg NGF per kg), with the higher-dose groups experiencing less pain and greater improvements than the lower-dose groups, the authors report.

Though there were trends towards improvement in cooling and vibratory sensation, the report indicates that only the higher-dose patients showed significantly improved pin sensitivity.

Thirty-four moderate or severe adverse events included 28 complaints of injection site discomfort, two cases of diarrhoea, and one report each of rash/urticaria, fatigue, impaired balance, and cough.

“Both the double-blind study and this open-label follow-up show symptomatic improvement in patients treated with NGF,” Dr. Schifitto said. “A phase III study in HIV sensory neuropathy would be needed to clearly define the efficacy of NGF in this population.”

Dr. Schifitto said that as far as he knows, South San Francisco, California-based biotechnology company Genentech Inc. “shelved NGF after the negative results of the diabetic neuropathy study.”

“The response to NGF in diabetic sensory neuropathy and HIV-associated sensory neuropathy are not necessarily comparable, because the pathological mechanisms involved may differ,” he said. “Therefore, the negative results of the phase III diabetic neuropathy study should not be extrapolated to HIV sensory neuropathy.”

Ref: Neurology 2001;57:1313-1316.

Source: Reuters Health

“We now routinely combine HAART and chemotherapy in clinical practice, ” Dr. Andrea Antinori from National Institute for Infectious Diseases Lazzaro Spallanzani in Rome told Reuters Health.

Although previous data suggested higher remissions and improved survival rates with non-Hodgkin lymphoma (NHL) during the HAART era, the authors point out that no longitudinal data are available yet.

Dr. Antinori and colleagues evaluated the impact of response to HAART on the response of NHL to chemotherapy in 44 patients during a 27-month longitudinal study at two AIDS clinical centres in Italy.

Twenty-four of the 36 patients who received HAART as prescribed had a virological response, the report indicates, and 18 patients also experienced at least a 30% increase in CD4 cell counts.

Twenty-three patients (52.2%) achieved a complete remission and five patients (11.4%) had a partial remission in response to chemotherapy, the authors report, whereas 16 patients (36.4%) showed progressive disease.

Complete remission was six times more likely among HAART virological responders, the results indicate, and any chemotherapy response was nearly 26 times more likely. In fact, virological response to HAART was the only variable independently associated with complete remission.

During their combination HAART-chemotherapy, patients experienced a mean -1.61 log10 copies/mL in plasma HIV RNA, the researchers note. Each log10 fall brought a 1.7-fold increase in the probability of achieving complete remission.

Overall 1-year survival probability was 49%, the investigators report, but the probability was 78% among HAART virological responders and 84% among those who achieved immunological restoration.

Toxicities from chemotherapy and HAART did not differ between virological responders and virological nonresponders or HAART-naïve patients, the report indicates.

“The main message, ” Dr. Antinori said, “is that the combination of HAART and chemotherapy, which is tolerable and feasible, is warranted for a better response to chemotherapy and to improve the survival of patients.”

“Another important point is that the chemotherapy itself does not negatively affect virological response during HAART and does not cause an irretrievable decline of the immune system, ” Dr. Antinori concluded.

Ref: Antinori A et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 2001;15:1483-1491.

http://www.ncbi.nlm.nih.gov/pubmed/11504980?dopt=Abstract

Source: Reuters Health

The doctors provided details on a 34-year-old man whose CD4+ count was 200 cells and whose viral load was “undetectable.” He had been taking highly active antiretroviral therapy (HAART) for about a year and had symptoms of herpes on his genitals for about five months. Doctors prescribed the following regimens one at a time to treat the herpes infection:

acyclovir – 1, 200 mg/day for one month

Valtrex – 2 grams/day for one month

Famvir – 1, 500 mg/day for one month

Because these drugs did not help, doctors then prescribed 5% imiquimod cream, which the man applied to his lesions and then washed off eight hours later. He did this three times in one week and then stopped the drug.

After four days, the pain from the herpes infection cleared. After one week, the lesions healed. The man has remained free from herpes lesions for at least one month and did not report any side effects associated with Aldara.

Imiquimod is licensed in Europe for the treatment of warts on the genitals and anus. This drug appears to work by stimulating CD8+ cells and other cells of the immune system in the skin to fight viral infections. The drug is currently being investigated for the treatment of certain types of skin cancer. It has also been used to treat another troublesome AIDS-related complication – mollusca lesions – caused by MCV (Mollusca contagiosum virus). Further research on imiquimod, and possibly more effective immune boosters such as resiquimod, is underway.

Imiquimod can cause skin irritation, rash and itching, among other side effects. Doctors are not sure if the drug will work for people with HIV/AIDS who have very low CD4+ counts. The team of doctors in New York suggests that imiquimod be tested in clinical trials to confirm its anti-herpes activity.

COMMENT

A related compound, resiquimod, is an the results of a Phase II clinical study with resiquimod (a more potent analogue of imiquimod) were presented in September, 2000 at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The results of this blinded, dose ranging study in patients with frequently recurring genital herpes showed time to first recurrence extended approximately 3 times (resiquimod gel 169 days compared to vehicle 57 days) and proportion of patients without a genital herpes recurrence in 6 months increased approximately 4 times (resiquimod gel 32% compared to vehicle 6%).

Phase III studies with resiquimod (R-848) are under way in North America and Europe. If these Phase III trials proceed on track, 3M Pharmaceuticals expects to file licensing dossiers for this new molecule globally in Q2 2004. The first launch for this new molecule could be as early as Q2 2005 in the United States. Other launches would proceed globally based on individual country registration and reimbursement feedback to 3M Pharmaceuticals.

Both imiquimod and resiquimod are hypothesised to work by stimulating local production of interferons leading to autovaccination of HSV.

Ref: Gilbert J et al. Topical imiquimod for acyclovir-unresponsive herpes simplex virus 2 infection. Archives of Dermatology 2001;137:1015-1017.

http://www.ncbi.nlm.nih.gov/pubmed/11493093?dopt=Abstract

Source: CATIE News.

CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto. From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE’s Information Network at http://www.catie.ca/

Doctors at the University Hospitals of Cleveland, Ohio, reported details about their unusual and successful treatment of a KS lesion. According to their report, a 45-year-old man who developed a KS lesion on his foot sought medical care. Repeated blood tests revealed that he was HIV negative but was infected with HHV-8, the cause of KS. His CD4+, CD8+ and other blood counts were within the normal range. Laboratory analysis confirmed that his tumour was indeed KS. Doctors then prescribed oral ganciclovir, 1 gram three times daily for three months (because of its possible anti-HHV-8 activity), but this had no effect on his lesion.

After this failure, other options were considered, including injecting the lesion with chemotherapy, interferon, cidofovir (Vistide), foscarnet (Foscavir), Panretin (alitretinoin), and radiation therapy. None of these options were selected because the lesion was growing very slowly and the side effects of therapy were not “acceptable to the patient.” Instead the patient and his doctors chose an unconventional approach – low-dose oral shark cartilage.

Shark cartilage in the lab

In lab experiments with tumours and mice with cancer, shark cartilage and its extracts appear to block the growth of blood vessels that feed a tumour. KS tumours are often associated with a rich network of blood vessels, so perhaps its not surprising that the research team chose to study shark cartilage: therapies that have the potential to reduce blood vessel growth could help “starve” the KS tumour.

Researchers monitored the man as he took shark cartilage at a dose of 1, 875 mg twice daily for the first three months. The dose was then changed to 1, 500 mg three times daily for another 18 months.

After three months, the lesion began to shrink and its colour faded. By the sixth month it became thinner and it became almost impossible to notice. No side effects were reported during this time. The man continues to take shark cartilage (Dr. Scot Remick, personal communication).

Notes about the dose

Although shark cartilage has been tested in people with cancer, those subjects had received chemotherapy and also had “advanced” cancers of the breast, colon and lungs. Moreover, shark cartilage was given at a higher dose for only three months. In experiments where chemotherapy is used to attack the blood vessel networks that nourish a tumour, the best results were obtained when researchers used low-dose chemo for longer periods of time.

It is possible that the KS tumour in this patient could have simply disappeared on its own – spontaneous regression. Until a controlled clinical trial takes place, we cannot be certain about the effectiveness of shark cartilage. Future research needs to examine issues relevant to people with HIV/AIDS, such as drug interactions and the additional effect of chemotherapy. Shark cartilage used in this man’s treatment was distributed by Swanson Health Products and General Nutrition Center and cost between $1.08 and $1.32 US per day.

Ref: Hillman JD et al. Treatment of Kaposi sarcoma with oral administration of shark cartilage in a human herpesevirus 8-seropositive, human immunodeficiency virus- seronegative homosexual man. Archives of Dermatology 2001;137:1149-1152.

http://www.ncbi.nlm.nih.gov/pubmed/11559209?dopt=Abstract

Source: CATIE News.

CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto. From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE’s Information Network at http://www.catie.ca

Dr. Jacques Cadranel, of Hôpital Tenon, and associates report that this phenomenon occurred in three patients out of 65 with PCP treated at a single centre between 1996 and 2000. The severe PCP, which in all three cases was the first sign of HIV infection, resolved after 15 days of parenteral cotrimoxazole and steroids.

HAART was initiated within 1 to 16 days of PCP diagnosis. As reported in the American Journal of Respiratory and Critical Care Medicine for September 1, acute respiratory failure with high-grade fever developed within 7 to 17 days. Lung biopsies and bronchoalveolar lavage revealed severe nonspecific pulmonary inflammatory foci surrounding rare P. carinii cysts.

HAART was interrupted in two patients and steroids were reintroduced in two. All three patients recovered from the respiratory failure.

Dr. Cadranel’s team reports that HAART initiation led to marked decreases in plasma viral load, but that “circulating CD4+ cell counts did not increase in parallel, suggesting possible CD4+ cell sequestration in the lungs and their participation in the acute pulmonary reaction.”

Ref: Wislez M et al. Acute Respiratory Failure Following HAART Introduction in Patients Treated for Pneumocystis carinii Pneumonia. Am J Respir Crit Care Med 2001;164:847-851.

http://www.ncbi.nlm.nih.gov/pubmed/11549544?dopt=Abstract

Source: Reuters Health

Valcyte is a prodrug of Roche’s existing anti-CMV treatment, Cymevene® (ganciclovir), developed in response to the need for more convenient and patient-friendly administration of ganciclovir. The introduction of Valcyte means that patients with acute CMV retinitis will only have to take two Valcyte tablets twice-daily rather than receive two IV infusions a day. For patients receiving maintenance treatment aimed at preventing relapse or progression of CMV retinitis, two Valcyte tablets once-daily will replace a daily Cymevene IV infusion or up to 12 Cymevene capsules daily on a three times daily basis. Cymevene is currently the most widely prescribed anti-CMV medication worldwide.

The approval was supported by clinical studies that show Valcyte tablets have comparable efficacy for induction therapy when compared to intravenous Cymevene. In the U.S. Valcyte received approval following priority review from the Federal Drug Administration, a designation reserved for treatments deemed to represent potentially major advances in healthcare.

Source: Roche Pharmaceuticals press release

COMMENT

Valganciclovir has been available in the UK through special licence sales similar to a named-patient programme.

Doctors should contact Deborah Vincent on 01707 367857 at Roche laboratories directly to register patients for this programme and for further information.

In a study reported in the June 10th issue of AIDS Research and Human Retroviruses, Dr. Lynn A. Riddell, from Barts and the London NHS Trust, and colleagues randomised 84 patients with advanced HIV disease to received thrice weekly rIFN-gamma treatments or placebo for 48 weeks.

The researchers found that rIFN-gamma-treated patients tended to develop fewer opportunistic infections than placebo-treated patients. The immune therapy was particularly effective in reducing the incidence of Candida, herpes simplex, and cytomegalovirus infections. A nonsignificant improvement in survival was also noted with rIFN-gamma treatment.

While several side effects such as headache, fatigue, and rigors were linked to rIFN-gamma therapy, they were reversible, the investigators state. In addition, the immune therapy did not seem to promote HIV activation.

“IFN-gamma has been shown to protect monocytes from HIV infection, down-regulates CD4 on lymphocytes, potentially reducing infectability, and inhibits HIV replication by inducing a defective particle maturation,” the authors point out. “These mechanisms may counteract others that increase HIV replication.”

Dr. Riddell’s team believes that although the treatment differences failed to reach statistical significance, they do warrant consideration of further rIFN-gamma trials.

Ref: AIDS Res Hum Retroviruses 2001;17:789-797.

Source: Reuters Health

Dr. Alejandro Olive and colleagues from Hospital Universitari Germans Trias i Pujol in Barcelona studied 74 HIV-infected patients with osteoarticular manifestations. Twenty-three percent of the patients had septic arthritis, with Staphylococcus aureus identified as the most common microorganism, according to the team’s report in the April issue of the Journal of Rheumatology.

In addition, 12.2% of the patients had soft tissue infections, 8.1% had spondyloarthropathies, 12.2% had lymphomas, 8.1% had osteomyelitis and 32.4% had other miscellaneous conditions, which included arthralgia, gout, tendinitis and osteonecrosis.

Among patients with septic arthritis, the mean CD4+ count was 164.7 cells/mm3, for those with soft tissue infections it was 127.1 cells/mm3, and for patients with spondyloarthropathies it was 245.8 cells/mm3, Dr. Olive’s team found. Among patients with lymphoma, the mean CD4+ count was 132.8 cells/mm3 and for those with osteomyelitis it was 233.6 cells/mm3.

Osteoarticular infections, the investigators found, always appeared when CD4+ counts were below 200 cells/mm3, and pyomyositis and lymphoma appeared when CD4+ counts were below 150 cell/mm3. “This suggests,” they say, “that musculoskeletal infections occur when HIV infection is advanced and that CD4+ counts may be predictive for particular musculoskeletal manifestations.”

Ref: J Rheumatol 2001;28:802-804.

Source: Reuters Health

The researchers retrospectively studied 1,280 patients seen between July 1990 and June 1999, relating oral findings to medication use, immune function and viral load. They focused on three key oral lesions-oral candidosis, hairy leucoplakia and oral warts-and studied their relation with antiretroviral therapy, with or without the use of protease inhibitors, adjusting for CD4 count and viral load. Treatment that included one or more antiretroviral agents including non-nucleosides but excluding protease inhibitors was defined as antiretroviral therapy (ART), while treatment that included one or more antiretroviral agents plus protease inhibitors was defined as HAART. During the 9 12-month periods, oral candidosis, hairy leucoplakia and Kaposi’s sarcoma decreased substantially, whereas the frequency of aphthous ulcers did not change. There was an increase in the occurrence of salivary gland disease and a “striking increase” in the rate of warts: three-fold for patients on ART and six-fold for patients on HAART.

The researchers said that “the increase in the occurrence of oral warts, and its apparent association with both ART and protease inhibitors, is somewhat unexpected, although a link has been suggested previously. Some other opportunistic infections, most notably TB and cytomegalovirus retinitis, can also recur among patients receiving HAART as HIV viral loads fall and CD4 cell counts improve. “The reconstitution of the immune system might be functionally incomplete and its effectiveness might therefore vary with regard to different potentially pathogenic micro- organisms,” the researchers said. “This situation could lead to the development of oral warts, and perhaps skin warts, in the context of an overall reduction in opportunistic infections. The oral warts we see in HIV-positive individuals, including those on HAART, present substantial management challenges. The warts are often extensive and progressive and recur after removal. So far, no effective cure has been established. Thus they cause substantial discomfort and aesthetic problems.”

Ref: Deborah Greenspan; Alison J Canchola; Laurie A MacPhail; Behnaz Cheikh; John S Greenspan. Lancet (05.05.01) Vol 357; No 9266: P 1411-1412.

Source: CDC HIV/STD/TB Prevention News Update

It is known that the immunosuppression associated with HIV infection and AIDS leads to a significantly increased risk for Kaposi’s sarcoma (KS), non-Hodgkin’s Lymphoma (NHL) and cervical cancer. It is not well known, however, whether other malignancies are also associated with HIV disease and AIDS.

In a study published in the Journal of the American Medical Association, researchers from the AIDS-Cancer Match Registry Study Group evaluated cancer data from 302,834 adult patients, 15 to 69 years of age, diagnosed with AIDS between 1978 and 1996. The study included all cancer types, except non-melanoma skin cancers. The relative risk of cancer was determined for 60 months before to 27 months after AIDS onset. The relative risk for each cancer was defined as the ratio of observed to expected cancers derived from contemporaneous population-based incidence rates.

As expected, the investigators found that KS, NHL and cervical cancer occurred at significantly higher rates in HIV-infected patients. KS occurred in 9.9% of men and 0.8% of women. Among men, the incidence of KS was found to be highest in gay men, who had a relative risk of 267.2. Among women, KS was highest among those who were infected by a bisexual man, with a relative risk of 2044.2. NHL occurred in 3.4% of men and 1.5% of women, with relative risks of 71.7 and 88.4, respectively. Cervical cancer occurred in 0.7% of women, with a relative risk of 5.2.

Four thousand four hundred and twenty-two invasive cancers, other than KS, NHL and cervical cancer, occurred in this population. The overall relative risk of these cancers was 2.7, and this higher risk was present in both HIV-infected men and women. 6 cancers appeared to be potentially influenced by the immunosuppression associated with HIV infection and AIDS. These included Hodgkin’s disease, lip cancer, lung cancer, soft tissue malignancies, penile cancer, and testicular seminoma, with relative risks of 11.5, 3.1, 4.8, 3.3, 3.9 and 2.0, respectively. In this population, lung cancer was the most frequently diagnosed non-AIDS-defining cancer.

This study rather convincingly shows that when compared with the general population HIV-infected patients are at increased risk of cancer. This increased risk is highest regarding the AIDS-related cancers, KS, NHL and cervical CA, but also extends to other cancers. Some of these cancers are almost certainly related to well-defined risk factors other then HIV-infection, including smoking (lung and lip cancers), and infection with human papillomavirus (cervical and penile cancers), human herpesvirus 8 (KS) or Epstein-Barr virus (Hodgkin’s disease), but immunosuppression appears to play a role as well, with its overall impact dependent upon the cancer type.

Finally, these data, collected prior to the widespread use of HAART, may actually underestimate the incidence of these and other cancers in HIV-infected patients. As some studies have demonstrated, cancer may become an increasingly important problem as survival time increases in HAART-treated, HIV-infected patients.

Reference: M Frisch and others. Association of Cancer With AIDS-Related Immunosuppression in Adults. JAMA. 2001; 285:1736-45.

Source: http://www.hivandhepatitis.com

Copyright 2001 by HIV and Hepatitis Treatment Advocates and HIV and Hepatitis.com. All Rights Reserved.

Dr. William R. Robinson from Harrington Cancer Center in Amarillo, Texas and colleagues compared the clinical outcomes of 56 HIV-positive women with CIN to those of 62 similar women without HIV infection.

Persistent or recurrent and progressive CIN after excisional therapy was significantly more common among HIV-positive women than among HIV-negative women, the authors state.

In the HIV-positive group, low CD4+ cell count and margin involvement of loop excision specimens were risk factors for recurrence. HAART use, was associated with lower recurrence or persistence rate and a lower progression rate.

“The finding that HIV-positive women had higher rates of CIN recurrence and progression than HIV-negative women has been shown in studies before,” Dr. Robinson told Reuters Health. “The new finding was that HIV-positive women who received HAART had much lower rates of CIN recurrence and progression than HIV-positive women who did not receive HAART,” he stated.

“Other studies have shown that HIV-positive patients with KS or non-Hodgkin’s lymphoma do better when they receive HAART, irrespective of the specific treatment that they receive for their malignancy,” Dr. Robinson pointed out. “We wondered if the same might hold true for CIN.”

Dr. Robinson believes that “the message for physicians is that HIV-positive women who have cervical disease should be motivated to take HAART because it improves the outcome of their cervical disease as well as their overall health.”

Ref: Am J Obstet Gynecol 2001;184:538-543.

Source: Reuters Health

In a 12 to 1 vote, the Antiviral Drugs Advisory Committee agreed that valganciclovir is safe and effective as induction therapy for CMV. The panel voted unanimously that Roche’s data support use of valganciclovir for long term maintenance therapy to treat the AIDS-related infection.

If the FDA follows the panel’s recommendation, which it almost certainly will, valganciclovir will be the first orally-administered CMV therapy approved for both induction and maintenance therapy. Currently, patients newly-diagnosed with the disease are generally treated with injectable induction therapies – including Roche’s Cytovene-IV (ganciclovir) – requiring long infusions that can carry the risk of sepsis.

The FDA approved an oral formulation of ganciclovir in 1994 for maintenance therapy only. Valganciclovir, Roche’s new oral drug, is the pro-drug of ganciclovir and “is rapidly converted into ganciclovir in the body,” according to the company.

Roche’s Dr. James Thomas commented that the advent of HAART therapy for AIDS patients, while undeniably good news overall, has made it more difficult to develop drugs to treat AIDS-related infections.

HAART therapy, which combines a trio of AIDS drugs, has dramatically reduced the incidence of opportunistic infections, including CMV retinitis, making it harder to recruit patients for studies, he noted. In addition, proving long term efficacy has become challenging, since AIDS-related infections disappear relatively quickly in patients on HAART therapy, he said.

As a result, Roche relied on data from a 4-week, 370-patient induction therapy study to show that its oral therapy was comparable to injectable Cytovene. The time period was deemed long enough to show safety and efficacy, but short enough to prevent positive effects of HAART therapy from biasing the findings.

Some panellists were concerned that the company had not demonstrated valganciclovir’s long term efficacy versus a comparator drug, but Roche representative Dr. Mary Jean Stempien argued that the firm had crossed the “highest hurdle” by demonstrating efficacy at the induction phase.

Roche’s study, which involved a “direct comparison with the standard of care” plus pharmacokinetic data, was sufficient to support the drug’s efficacy for CMV maintenance therapy, she told the committee.

The issues that arose at Tuesday’s meeting regarding data sufficiency are likely to come up frequently in evaluating drugs for AIDS-related infections in the era of HAART therapy, panel members agreed. The therapy has triggered a “real paradigm change” in the way drugs for AIDS-related conditions are studied, noted panel chair Dr. Roger Pomerantz, professor at Philadelphia-based Thomas Jefferson University.

The panel recommended that Roche conduct phase IV studies of valganciclovir to evaluate the product’s efficacy in light of factors including age and gender: the vast majority of patients in Roche’s clinical studies so far have been male.

“I would like to see a phase IV trial [in which] HAART patients are segregated in some way to see if there truly is efficacy with valganciclovir in the HAART era,” maintained panellist Dr. Ram Yogev, of Chicago-based Children’s Memorial Hospital.

The panel also suggested that Roche’s post-marketing studies should address possible drug-drug interactions and assess optimal dosing for CMV maintenance therapy.

Source: Reuters Health

COMMENT

A long awaited expanded access programme for valganciclovir opened in France last month. No similar programme will be available in the UK until June 2001, by which time the drug may already approved by the EMEA.

Docosanol has shown activity against a broad spectrum of lipid-enveloped viruses in vitro, is currently approved by the US Food and Drug Administration for the topical treatment of recurrent oral-facial herpes simplex infections.

Dr. Michael J. Scolaro, from the Scolaro Medical Coalition, in Beverly Hills, California, and colleagues assessed the safety and efficacy of topical docosanol 10% cream in 10 HIV-1-positive KS patients treated with the medication five times daily for 4 weeks. At the end of the 4-week period, all patients elected to have their treatment extended for up to 35 weeks.

The researchers point out that the current study’s ability to determine efficacy is limited because it was an open-label study without a placebo group and because patients did not discontinue their established antiviral regimens. In addition, ACTG response criteria were not employed.

“The study has nevertheless shown that docosanol can be used safely in immunocompromised individuals and that it may exert clinical benefits on cutaneous KS lesions in HIV-positive patients, indicating that docosanol 10% cream merits further investigation as a topical therapy for the treatment of cutaneous KS disease,” Dr. Scolaro’s team concludes.

Ref: AIDS Res Hum Retroviruses 2001;17:35-43.

Source: Reuters Health

In the present study, the authors assessed the pharmacokinetics, safety and efficacy of oral ganciclovir in 36 CMV patients, ages 6 months to 16 years, who were severely immunocompromised by HIV infection. According to the paper, administration of 30 mg/kg ganciclovir at 8-hour intervals achieved serum drug levels similar to those used for maintenance treatment of CMV retinitis in adults.

The investigators report that doses between 10 and 50 mg/kg per 8 hours were generally well tolerated. About 20% of patients withdrew from the trial because of intolerance of the large volume of suspension or number of capsules. No patient withdrew because of neutropenia, but four required granulocyte colony-stimulating factor.

The study team notes that CMV recurrence or new-onset disease occurred in seven and three children, respectively. Of the three children with new-onset disease, one developed ganciclovir resistance, another had resistant CMV at the start of the study, and the third had wild-type virus. In light of their findings, the study team concludes that “oral ganciclovir at least 30 mg/kg every 8 hours, either as a suspension prepared in a pharmacy or as capsules, should provide effective prophylaxis of CMV disease in children.”

In interview, Dr. Frenkel said she would not recommend routine use of oral ganciclovir for children with CMV/HIV infection. “Fortunately, treatment of HIV with combinations of antiretroviral drugs appears to result in the improvement or maintenance of sufficient anti-CMV immunity such that CMV disease rarely occurs,” she said. “In severely immunocompromised children, however, I would consider prophylaxis with ganciclovir if they are infected with CMV.”

Ref: J Infect Dis 2000; 182:1616-1624.

Source: Reuters Health

Overall, 53.2% of patients had HIV-related oral lesions. Oral candidiasis was the most common type of lesion, accounting for 34.4% of all cases. Other lesions included hairy leucoplakia (26.6%), xerostomia (15.5%), herpes simplex labialis (1.9%) and periodontitis-gingivitis (0.6%). No cases of oral Kaposi’s sarcoma were identified. Male patients who reported sexual contact with other males had the lowest rate of oral lesions, according to the report, published in the December issue of AIDS Patient Care and STDs. The highest rates of HIV-associated oral lesions were observed in intravenous drug users and patients with viral loads higher than 10,000 copies/mL and CD4+ count below 200 cells per microliter.

“To the best of our knowledge, this is the first time that the prevalence of oral lesions in a population of patients with AIDS undergoing HAART, including protease inhibitors, is reported,” Dr. Gaitan-Cepeda’s group writes. The greatest decrease in prevalence was seen in lesions associated with viral infections, they add. “Although we do not have a valid explanation for this, it seems likely that the combination of reverse transcriptase inhibitors and protease inhibitors…improved the immunologic conditions of the patients,” they suggest.

Ref: AIDS Pat Care STDs 2000; 14:627-635.

Source: Reuters Health

As they report in the December issue of the Journal of Medical Virology, treatment increased the CD4+ T-cell count, decreased the HIV plasma load, and decreased the detection rate of HHV-8, while the titres of anti-HHV-8 IgG were unchanged. The changes were all statistically significant except for HIV plasma load, where the changes approached significance. In addition, the changes occurred whether protease inhibitors were introduced at the same time as reverse transcriptase inhibitors or later.

“Treatment with HIV-1 protease inhibitors is therefore associated with the clearance of HHV-8 DNA from peripheral blood of HIV-infected patients,” Dr. Teo and colleagues conclude. “The concomitant decrease in the HIV plasma load and increase in the peripheral CD4+ cell count suggest that an amelioration in the immune defect following reduction in the burden of HIV-1 infection is responsible for the clearance of HHV-8 by protease inhibitors.”

However, they stress that drugs that specifically target HHV-8 replication are still needed, which “may also benefit patients affected by forms of Kaposi’s sarcoma that are not AIDS-related, in particular the aggressive varieties of endemic (African) Kaposi’s sarcoma.” 12.27/00

Ref: J Med Virol 2000; 62:416-420.

Source: Reuters Health

Although C. albicans is one of the infections that generally quickly improve and resolve following the immune response after HAART, in patients whose HIV progresses due to a failing salvage regimen Candida can become a life threatening condition and azole resistant infection is an increasing clinical problem. This anecdotal report from the Gartnavel General Hospital in Glasgow, presented evidence of the successful use of interferon-gamma to treat azole resistant oropharyngeal candidiasis and advanced HIV disease.

The 31 year old HIV positive patient presented with recurrent oropharyngeal Candida albicans infection which was known to be clinically and microbiologically resistant to azole therapy (fluconazole MIC > 128 mg/l and itraconazole MIC > 16 mg/l). Previous episodes of C. albicans infection since his HIV diagnosis in 1992 had been treated successfully with courses of fluconazole, itraconazole and ketoconazole.

His CD4 count was 7 cells/mm3 (1%) and viral load was 48,000 copies/ml. He was highly antiretroviral experienced and at time of presentation was taking abacavir, 3TC and d4T. The patient refused therapy with intravenous amphotericin and therefore, interferon-gamma (1 mg sub-cutaneously three times weekly) was used to attempt to stimulate macrophage function (topical amphotericin and nystatin treatment was continued). Within 3 weeks of commencing this therapy there was a dramatic improvement in symptoms and signs of oropharyngeal candidiasis.

After 4 months interferon-gamma was discontinued and within 4 days there was recurrence of his symptoms. Interferon-gamma treatment was therefore re-introduced successfully.

The mechanism for the antimicrobial effect of IFN-g suggested in this study included macrophage activation, stimulation of antigen presentation, regulation of leucocyte – endothelium interaction and effects on cell proliferation and apoptosis. IFN-g increases the production of reactive oxygen radicals which then increases the candidiacidal activity of granulocytes.

Ref: Bodasing N, Seaton RA et al – Interferon-gamma in resistant oropharyngeal candidiasis in an HIV positive patient. Poster 383. 5th Intl Congress on Drug Therapy in HIV Infection, Glasgow. 22-26 October 2000.

As we are all well aware the incidence of opportunistic infections (OIs) has fallen dramatically since HAART became available in 1996, despite some evidence of declining use of OI prophylaxis [1]. While the data indicates that the decline has levelled off somewhat this should not have been unexpected and probably is due to a combination of factors, including HAART failures and refusal of or non adherence to HAART and prophylactic medications. Several studies, including some presented at this conference, indicate that the patient is at minimal risk for contracting certain opportunistic infections if he or she achieves and maintains significant immunologic reconstitution with HAART. This data has existed for some time and several reviews containing recommendations regarding prophylaxis discontinuation have been published [2] and the DHHS prophylaxis for OI guidelines has been revised to recommend prophylaxis discontinuation in certain OIs when HAART reconstitution occurs.

During a plenary session on OIs, Dr. HansJakob Furrer from Switzerland discussed “Opportunistic infections: what’s new?” [3]. He began by recognizing the remarkable decline in OI incidence and by making the point that achieving a CD4+ cell count greater than 200 cells/mm3 and maintaining that level for 6 months is a valuable marker for a significant decrease, and perhaps elimination, of the risk of almost all OIs. This level is likely to be sufficient to prevent Pneumocystis carinii pneumonia (PCP) and Toxoplasmosis, [4, 5], but even lower levels of reconstitution may be equally protective against other OIs and some cancers. Patients with CD4 cell counts greater than 100 cells/mm3 appear to be at minimal risk for cytomegalovirus (CMV), Mycobacterium avium Complex (MAC) and Cryptococcosis and CNS lymphoma, major causes of morbidity and mortality in the AIDS population [6, 7].

Taking this concept one step further, Dr. Furrer discussed prophylaxis discontinuation. As cited above, there are now several studies that strongly indicate that prophylactic medications for both primary and secondary infections can be stopped when patients regain and hold for 3-6 months sufficient CD4+ cells to be above the threshold for starting prophylaxis. This is very encouraging data, especially since the pill burden and side effects of some prophylactic medications may compromise the patients ability to be strictly adherent to their HAART regimen. Despite this data, some of which Dr. Furrer has published, he remains somewhat cautious regarding discontinuing prophylaxis for certain conditions, stating that the discontinuation of prophylaxis against PCP, CMV and MAC may be safe in some patients but that it needs further evaluation.

While further data would be nice, in view of the studies cited above, I am not sure I fully agree with Dr. Furrer’s hesitation, especially in patients with a CD4+ cell count well above the threshold for prophylaxis for more than 6 months and with a viral load less than 50 copies/mL. Of course, there still remains some risk. Careful monitoring is required and patients who are barely above a cut-off ought to be continued on prophylaxis until there is more data regarding safety. But, weighing the risk and benefit of continuing sometimes poorly-tolerated and burdensome prophylactic or treatment regimens, most patients and physicians are now generally siding with discontinuation where the studies indicate that it is generally safe.

Dr. Chris Boshoff from London discussed the aetiology of Kaposi’s sarcoma (KS) and it’s association with Kaposi’s sarcoma-associated herpesvirus (“KSHV” or “HHV-8) [8]. This association has become so strong that there is now little doubt that KSHV is involved in inducing the proliferation of the tumour cells that cause KS in HIV-infected patients. Further, there is some demographic data that strongly indicates that KSHV may also be significantly involved in classic KS. Several latent proteins produced by KSHV seem to be the critical causative agents and research is underway to determine how to decrease or modify these proteins to interfere with their role in cell proliferation and transformation. Further, many of us have had patients with advanced KS that have improved with HAART and data supports this clinical finding. So, as with many opportunistic diseases, KS can resolve with partial immune system restoration, although the exact level of restoration required is unclear and may vary from patient to patient.

Several presenters during this plenary session discussed CMV disease. Dr. Jane Deayton from London reported on a prospective study that evaluated the efficacy of HAART in clearing CMV viraemia [9]. The median CMV viral load in patients prior to HAART was 4.90 log10 copies/mL. After 6 months of HAART therapy, this viral load had declined 2.6 log10 copies/mL, which equated to a mean antiviral efficacy of the regenerating immune system of 61.5%, which can be compared to that of gangciclovir’s mean efficacy of 91.5% against wild type CMV. Dr. Deayton believes that this finding of efficient viral clearance by a regenerating immune system lends support to the concept that the reconstituted immune system is capable of CMV control without CMV antiviral therapy. She noted, however, that the extent and time course of this clearance may be highly variable and dependent on a number of factors, including the number of CMV-specific precursor cells which remain prior to HAART and the rapidity of their differentiation.

The findings of Dr. Deayton explain the findings of several clinical studies, including one presented by her at this conference [10], indicating that primary and secondary CMV therapy can be safely discontinued in patients with a CD4+ cell count greater than 100 cells/mm3 on HAART; however, it also should encourage continuation of that therapy until the patient is clearly in the safety zone of CD4+ cell count for a significant period of time. Further, as the study by Dr. Deayton shows, patients who have CMV therapy discontinued need to be monitored carefully for evidence of a recurrence of their retinitis or viraemia. Three patients in Dr. Deayton’s study had recurrence of their CMV viraemia, one because of neutropenia associated with hydroxyurea and 2 who had a virologic failure of their HAART regimen, and this was associated in one patient with CMV resistance. Therefore, Dr. Deayton recommends genotyping of CMV for resistance mutations if treatment of CMV disease becomes necessary following HAART failure.

Finally, to end on a note of caution, we have all seen or heard of a patient that had an OI such as CMV retinitis despite having recovered a CD4+ cell count that should have taken them out of risk for that disease. Most of us are also familiar with the data that indicates that certain holes in the patient’s immunologic repertoire may persist, despite significant immune reconstitution. Dr. Sung-Chin Pan from Taiwan presented data indicating that some patients that have a marked rise in their CD4+ cell count may still lack the CMV-specific CD4+ cell reactivity necessary to prevent or control CMV disease [11].

He proposed that post-HAART CMV retinitis may be due to a poorly reconstituted immune system response to CMV and proposed the testing of CMV-specific immune reactivity in high-risk patients who may benefit from continued CMV prophylaxis or treatment.

This is certainly a good suggestion and may have application to all prophylaxis discontinuation; however, most clinicians will not have this testing available on a routine basis and cost-effectiveness will certainly be at issue given that most patients appear to reconstitute adequately against the common OIs. An alternative, but not as elegant proposal, is to continue a high degree of vigilance for OIs in all patients who reconstitute with HAART and take prompt action if OI symptoms or signs appear.

References:

1. Tarwater P, Detels R, Margolich J, Phair J, Munoz A. The impact of antiretroviral therapy (ART) on the incidence of opportunistic infections (OIs) as presenting and secondary occurrences. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract TuPeB3138.
2. Boyle BA. Can OI Prophylaxis Be Stopped in Patients Responding to HAART? The AIDS Reader. 1999; 9(4):240-245.
3. Furrer H. Opportunistic infections: what’s new? In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract PL5.1.
4. Mussini C, Pezzotti P, Borghi V, et al. An open, controlled, randomized study on discontinuation of secondary prophylaxis for Pneumocystis carinii Pneumonia in patients with AIDS. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract TuPeB2278.
5. Lopez J, Miro J, Pena J, et al. Discontinuation of secondary Pneumocystis carinii Pneumonia prophylaxis in HIV-1 infected patients after immunological recovery with HAART. Results of a prospective, randomized and multicentric trial. In: Program and Abstracts of the 13th International AIDS Conference, July, 2000, Durban, South Africa. Abstract MoPeB2288.
6. Mussini C, Pini R, Borghi V, et al. Discontinuation of Secondary Prophylaxis for Cryptococcal Meningitis in AIDS Patients Receiving HAART. In: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September, 2000, Toronto, Canada. Abstract 1912.
7. Berengeur J, Gonzalez J, Pulido F, et al. Discontinuation of Secondary Prophylaxis in Patients with CMV Retinitis Who Have Responded to HAART. In: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September, 2000, Toronto, Canada. Abstract 2053.
8. Boshoff C. Kaposi’s sarcoma herpesvirus: from biology to pathogenesis. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract PL5.3.
9. Deayton JR, Sabin C, Johnson M, et al. Efficacy of the regenerating immune system in the inhibition of CMV replication after highly active antiretroviral therapy (HAART). In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract PL5.4.1.
10. Deayton JR, Shannon-Lowe C, Wilson P, et al. Recurrence of CMV viraemia and development of anti-CMV drug resistance in patients receiving highly active antiretroviral therapy for CMV retinitis. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract PL5.4.2.
11. Sung-Chin Pan, Szu-Min Hseih, Chien-Ching Hung, et al. The correlation between the development of cytomegalovirus retinitis and the cytomegalovirus-specific immunologic reactivity of T-cells. In: Program and Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection, October, 2000, Glasgow, Scotland. Abstract PL5.5.

The advent of antiretroviral therapy has clearly revolutionised the lives of those living with HIV disease. The successful use of HAART has led to a decline in incidence of opportunistic infections and tumours, and allowed many individuals who were staring at a severely shortened life span to lead lives of not only increased quantity, but also quality. Sullivan [1] presented data from CDC Atlanta showing a decline in opportunistic infections. From 1993 – 1998 there was a statistically significant decline in opportunistic infection in all evaluated groups, although from 1996 – 1998 there was only a significant decline in homosexual and intravenous drug using men. However, data from the University of California, presented by Jacobson [2] showed clearly that patients continue to die of AIDS related conditions, and by no means is the war against HIV over. In this study the strongest predictor of death remained a low CD4 count. Therefore although we strive for the “holy grail” of the undetectable viral load, it is important to realise that CD4 count remains the prime indicator for possibility of opportunistic infection.

In patients who do have a CD4 count response, there is now a significant amount of data that shows both primary and secondary prophylaxis against opportunistic infection may be stopped. In yet another presentation of the GESIDA study, the stopping of both primary and secondary toxoplasmosis prophylaxis has been shown to be safe. There has however been only limited data on stopping cryptococcal prophylaxis, previous data on small numbers presented by Nwokolo at BHIVA and by Alberg at the San Francisco Retrovirus Conference, has suggested that it may be safe to stop secondary prophylaxis against this condition.

Mussini et al add to this database [3] by presenting data on 24 individuals with cryptococcal meningitis. Mean CD4 count at the time of diagnosis was 42, and after a meantime of HAART of 22 months, the mean CD4 count has increased to 251 cells, though 6 patients had a CD4 count below 100. Cryptococcal neoformans meant that prophylaxis was stopped in 14 patients. Ten of whom had a serum cryptococcal antigen which was negative. After a mean time of follow up of 27 months there were no case of relapse of meningitis. There were similarly no cases in those who continued. As 6 patients had a CD4 count of below 100, but still had no evidence of cryptococcal neoformans disease relapse, the authors suggested that their HAART regime, which in all cases contained a protease inhibitor, may have had a direct anti cryptococcus effect. There is no data however to back this suggestion up in vitro. Although there is increasing amount of data on stopping cryptococcal meningitis prophylaxis, some patients may still be wary of doing so.

Many individuals affecting with HIV also have other sexually transmitted diseases. Perhaps the most common of these is infection with the human papilloma virus which has been linked to the development of cervical and anal neoplasia. In an important study by Luke [4] women who received antiretroviral therapy had a lower incidence of abnormalities on cervical smear than those women who did not receive highly active antiretroviral therapy, suggesting that immune reconstitution may be an important factor in reducing the incidence of these tumours.

Progressive multifocal leucoencephalopathy (PML) continues to occur in individuals. Although previously mostly described in those with low CD4 counts who had failed antiretroviral therapy, in our clinic we have seen patients who have developed PML despite reconstitution. Diagnosis of PML is made on typical MRI findings, and confirmed on testing of cerebral spinal fluid, for the causative agent the JC virus. Data from Diaz [5] suggests that quantitative measurement of JC did not give important information on extension of CNS lesions, or survival, suggesting that this test is no more useful than the standard qualitative testing.

In some areas of the world, infection with hepatitis B and hepatitis C is now one of the leading causes of morbidity and mortality for those living with HIV. Hepatitis B infection was shown to occur in a rate of approximately 40 times higher in those who are HIV positive, compared with a HIV negative controlled population. [6] They suggest that 3TC should be included in antiretroviral therapy regimens, in areas of high chronic hepatitis B virus infection. Although approximately 30% of patients at 3 years may seroconvert who receive 3TC as mono therapy, it remains unclear whether such a high level will be reached in those who are HIV positive.

Previous authors have reported that single agent use of 3TC may rapidly lead to the development of HBV 3TC resistance, and although there are reports of continuing sero conversions in patients with 3TC resistance, it would appear better that we learn our lessons from HIV disease and await the development of newer agents for the treatment of this condition, and then to give dual or triple therapy. There have been recent reports of a small number of patients responding to dual therapy with 3TC and famciclovir, although this approach awaits further confirmation.

There was some good news for those infected with hepatitis B, with reports of entacovir in the Woodchuck [7] and some early studies of emtricitabine [8] showing potential activity against this virus.

HIV-positive intravenous drug users are commonly co-infected with hepatitis C, and also homosexual men with HIV may have an incidence of over 10% of co-infection with this agent. It is well know that with hepatitis C individuals may have normal liver function tests, despite ongoing inflammation and development of fibrosis. Hoffman-Terry et al presented data on 10 patients with normal liver function tests who underwent biopsy [9].

8 of these patients, on whom many physicians may have felt biopsy inappropriate, showed substantial inflammation and fibrosis. It is therefore important that all HIV-positive patients are tested for co-infection with hepatitis C and that even those individuals with normal liver functions tests should consider undergoing biopsy. The aim of biopsy would be to try and choose which individuals may require and benefit from treatment. There has been some concerns over the treatment of hepatitis C with interferon (which may have many toxic side-effects), and ribavirin (which may have interactions with agents used in HAART). However the development of pegylated interferon which is interferon wrapped in polyethylene glycol, may reduced the toxicity and increase the efficacy of this agent. Studies are underway at several centres in London of this agent in co-infected patients, and physicians are encouraged to refer these patients for assessment to those centres of care.

References

1. Sullivan PS et al. Trends in AIDS-defining opportunistic illness diagnoses through 1998. Abstract I-1906. 40th ICAAC, Toronto, Canada, Sep 2000.
2. Jacobson S et al. Causes and predictors of death among people with HIV in the era of highly active antiretroviral therapy (HAART). Abstract I-1907. 40th ICAAC, Toronto, Canada, Sep 2000.
3. Mussini C et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in AIDS patients receiving HAART. Abstract I-1912. 40th ICAAC, Toronto, Canada, Sep 2000.
4. Luque AE et al. Effect of highly active antiretroviral therapy (HAART) on human papillomavirus (HPV) infection and disease among HIV-infected women. Abstract H-66. 40th ICAAC, Toronto, Canada, Sep 2000.
5. Diaz MS et al. Progressive multifocal leukoencephalopathy (PML): Is measurement of JCV load in CSF worthwhile? Abstract H-71. 40th ICAAC, Toronto, Canada, Sep 2000.
6. Kellerman SE et al. Incidence of chronic hepatitis B infection in HIV infected individuals and the protective effect of lamivudine; data from the adult/adolescent spectrum of HIV disease (ASD) project. Abstract H-1406. 40th ICAAC, Toronto, Canada, Sep 2000.
7. Colonno RJ et al. Long-term therapy with entecavir (BMS-200475) in the woodchuck model of chronic hepatitis infection. Abstract H-172. 40th ICAAC, Toronto, Canada, Sep 2000.
8. Robertson AT et al. Antiviral activity of emtricitabine in a phase I/II dose escalation trial, FTCB-101. Abstract H-1407. 40th ICAAC, Toronto, Canada, Sep 2000.
9. Hoffman-Terry M et al. Correlation of ALT with degree of liver damage by biopsy in HIV/HCV coinfected adults. Abstract H-175. 40th ICAAC, Toronto, Canada, Sep 2000.

“We were surprised by the fact that this condition was not as widespread as it might have been, given the number of severely immunocompromised patients,” Dr Babinchak told Reuters Health. On the other hand, most physicians seeing these patients “have probably seen 1 or 2 cases, but didn’t tie it all together,” he added. Exacerbations of opportunistic infections commonly seen in HIV infection have been described, the reviewers found. Onset has been reported in as little as 10 days after beginning HAART for a reaction to Cryptococcus neoformans or as long as a median of 43 weeks for cytomegalovirus vitreitis. “The speed with which immune reactivity recovers is an indication of how soon a patient may experience one of these inflammatory responses,” Dr Babinchak said.

The researchers also encountered reports of exacerbations of noninfectious autoimmune diseases and malignant conditions, such as Graves disease, systemic lupus erythematosus, and Kaposi sarcoma.

“The thing that characterizes [immune restoration syndrome] most,” Dr Babinchak said, “is that these are infections and conditions you would expect in people who are not doing well that are now being manifested in people who are doing well and who are presenting atypically.” Without well-controlled studies, therapy has to be individualized to the patient. Dr Babinchak explained that “Some cases clear with no therapy, just continuation of HAART. Some patients have undergone specific therapy directed at the infection, while for others, therapy was directed at the inflammatory component.” “The main thing to emphasize is that HAART should not be stopped in these situations,” he concluded.

Ref: Ann Intern Med. 2000:133:447-454.

Source: Reuters Health

Previous treatments had included liquid nitrogen, cantharidin, and tretinoin gel. Both patients had been on highly active antiretroviral therapy (HAART) for a median of 24 months.

The facial lesions were so disfiguring that the patients, an 8-year-old boy and a 4-year-old boy, experienced severe social isolation. The CD4 T-cell counts were 329 and 168 cells/µL, with viral loads of log 5.86 and log 5.63 HIV RNA copies/mL, respectively.

In an interview with Reuters Health, Dr Toro pointed out that “If you’re treating patients with HAART and the viral load doesn’t go down, then you are talking about a very resistant kind of situation.”

Cidofovir was mixed with Dermovan, a combination vehicle containing propylene glycol, and applied to lesions once a day, 5 days a week, for 8 weeks. Nonfacial and nonmucosal lesions were also occluded with adhesive tape for at least 12 hours at each application, Dr Toro told Reuters Health.

Five to 15 days after beginning the cidofovir treatment, both boys exhibited redness and painful erosions at the sites of the previous lesions, although surrounding skin was unaffected. “After 2 months of treatment, all the lesions that were treated showed complete clinical resolution,” the investigators write.

“The success of treatment is very dependent on the vehicle,” Dr Toro said. He explained that a commercially available preparation of 1% cidofovir uses a completely different vehicle. “For patients using that specific type, it didn’t work,” he said, adding that “It has to be compounded in this particular vehicle and it has to be fresh and it has to be kept refrigerated.

“We saw 1 of the boys 2 weeks ago, and there’s been no recurrence of any lesions after more than 2 years,” Dr Toro said.

Ref: Arch Dermatol. 2000;136:983-985.

Source: Reuters Health

Over a period of 40 months, Dr. Panganani Njobvu, of Stobhill Hospital, Glasgow, Scotland, and a colleague diagnosed psoriatic arthritis in 28 of 702 patients attending an arthritis clinic. Twenty-seven of these 28 patients were HIV-positive, they report.

In 20 patients, “arthritis and psoriasis developed simultaneously,” the authors state in their article, published in the July issue of the Journal of Rheumatology. Arthritis preceded psoriasis in four patients, and psoriasis preceded arthritis in the other three patients.

The authors report that most patients had extensive guttate-plaque psoriasis that did not remit with the onset of AIDS. The arthritis usually had an acute onset, “starting in the knees and/or ankle joint in 90% of patients during their first episode.” Amelioration of arthritis, although not psoriasis, typically occurred with onset of AIDS.

“This is the largest series yet recorded worldwide in association with HIV infection and this in a setting where psoriatic arthritis was extremely rare,” the authors comment.

Given the growing prevalence of psoriatic arthritis among HIV-positive black Zambians, the authors call for increased recognition of this condition “as an HIV-related disorder.”

Reference: J Rheumatol 2000;27:1699-1702.

HIV&Hepatitis.com

HPV (Human Papilloma Virus) is the virus that causes warts, including genital and anal warts, and chronic infection with certain strains of HPV has long been associated with precancerous changes that can lead to cancer of the cervix and rectum. Abnormal precancerous changes of both the cervix and anus can be detected by a simple Pap test. (The Pap test involves obtaining cells from the area with a wooden scraper, smearing the cells on a glass slide, staining the cells and looking for abnormalities with a microscope.) Two studies looked at HPV infection at different sites.

One study used a case-control design to evaluate risk factors for HPV in the mouth. In 1997-98, the frequency of oral lesions due to HPV at Grady Hospital in Atlanta was relatively stable, with 18 total cases seen over those two years. However, in 1999, 34 cases were diagnosed. When the investigators matched their 52 cases with 104 control patients who were similar but did not have HPV disease, they found three factors that were associated with an increased risk of oral HPV: antibody to hepatitis B, a decrease in the viral load in the six months prior to the HPV diagnosis, and African-American heritage. Most opportunistic diseases related to HIV have decreased in frequency in the HAART era, so the increased rate at which this problem is currently being seen is puzzling. Longer term follow-up is needed to sort this out.

HIV-positive teenagers between 13 and 18 years old were evaluated for anal HPV infection, early precancerous changes and other STDs. The group included 83 boys and 265 girls. There were different risk factors identified for anal HPV infection and precancerous changes of the anus between the sexes. In adolescent boys, anal HPV infection was associated with having anal sex and with the presence of anal warts.

In adolescent girls, anal HPV was associated with the presence of both anal warts and external genital warts, but not with anal intercourse. When the investigators excluded the presence of warts at any site, then the most important risk factor for boys was sexual orientation, and the most important factor for girls was having fewer than 200 CD4 cells. When they evaluated the risks for the development of precancerous changes of the anus, the risks were again somewhat different for the two sexes. For boys, these changes were associated with being HIV-positive and with detection of HPV, and for girls the changes were associated with having more than one sexual partner and with anal HPV. These data indicate that it is valuable to screen sexually active HIV-positive teenagers for both HPV and for precancerous changes.

Ref: Blumberg H.M., King M.D.,. O’Daniels C.M at al. Emergence of oral HPV infection among HIV-infected patients in the HAART era (TuOrB304)

According to Dr Andrew Grulich of the National Centre in HIV Epidemiology in Sydney, as long-term survival with HIV without progression to AIDS increases, cancers associated with only moderate degrees of immune deficiency are likely to become more important causes of morbidity in HIV.

‘The rates of anal cancer and HIV were higher in our study than US rates because 85% of the HIV-infected people in our study are gay men; and that percentage is much lower in the US,’ Dr Grulich said. His group identified a total of 1223 cancers (1,032 of which were AIDS-defining) among 7775 people with AIDS, while more than 200 cancers were identified through the HIV register.

The study used Australian national data on HIV/AIDS reported between 1983 and 1999, which were linked to data on cancer reported between 1982 and 1998. Cancers were included if they occurred 5 years prior and 2 years after an AIDS diagnosis (for AIDS matches) or after the date of HIV diagnosis (for HIV matches).

The researchers also found that rates of most common cancers, including lung and testicular cancer, did not increase. In addition, liver cancer rates were not higher either, despite high rates of hepatitis B and C infections among HIV-infected people in Australia.

‘This is the first linkage study on people with HIV who have not developed AIDS,’ Dr Grulich said. ‘As AIDS diagnoses decrease due to highly active antiretroviral therapy,’ he believes that ‘matching HIV and cancer databases will continue to become more important throughout the world.’

Source: Reuters Health

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Routine screening by pap smear and HPV typing would appear to be essential in the management of both HIV-infected men and women. Treatment of HSIL by other modalities in addition to surgical ablation should also be studied (ie. 5-FU creams).