Chelsea & Westminster Hospital.
Medical Consultant
|
CHANGES AHEAD!
|
Welcome to the first ATP DrFax of the new millennium. Importantly, this will also be the last issue of DrFax to be distributed by fax.
We believe that some stability in HIV treatments has now been achieved. Options for both first line and subsequent treatment are becoming more clearly defined and supported by both standards of care and guidelines. As such, rapid, "treatment alert" styles of communication by fax have become less critical. These factors combined with the low reliability and high cost of fax distribution have led to our decision to end the distribution of DrFax by fax.
The increased use and sophistication of email since our inception in 1996 has also encouraged us to concentrate our distribution on email. We recognise, however, that not all our readers have access to computers or email and will still be retaining printed copy and postal delivery.
If you currently receive DrFax by fax it is important that you complete and fax back the form attached to this issue to arrange either email or postal access. This will ensure a continued delivery to you.
With the demise of the fax edition we will be thinking of a more appropriate name for this document. Any suggestions gratefully received by the editor!
The next two issues will be reporting from the upcoming Retrovirus Conference in San Francisco. Paul Blanchard, Polly Clayden and Simon Collins will be joined by leading European clinicians in detailing the presentations from this important meeting.
|
ANTIRETROVIRALS
|
After combination antiretroviral therapy is discontinued, "...a rapid decline in detectability of the majority of primary mutations" occurs within 13 weeks, according to London-based investigators.
This finding is reported by Dr Helen L. Devereux and colleagues from Royal Free and University College Medical School, London, who evaluated the rate of decline in drug-resistant HIV-1 mutations in 25 patients after therapy was stopped.
It has been suggested that HIV-1 resistance mutations are less fit compared with HIV-1 wild type viruses, they explain in the December 24th 1999 issue of AIDS. If this is true, removal of the relevant drug may result in a rapid decrease of resistant viruses to undetectable levels. However, the "...durability of mutant viruses, once therapy is stopped, has not been systematically addressed as yet."
The study subjects had been treated with combination antiretroviral regimens, which included a mean of five different agents, for longer than 3 months. Dr Devereux's group performed genotypic HIV-1 resistance testing during the patients' most recent therapy regimen and after therapy was discontinued.
Overall, they observed a rapid decline in primary protease and reverse transcriptase gene mutations 13 weeks after therapy was halted. This included the protease mutations 30N, 46I/L, 82A, 90M and the reverse transcriptase mutations 70R, 184I/V, and 215 Y/F.
When genotypic testing was performed less than 2 weeks after therapy was stopped, 100% of the primary mutations were still detectable. However, this declined to 68% when testing was performed after a median of 6.4 weeks and to 15% after a median of 12.9 weeks.
The investigators found that the decline in the detectability of secondary HIV-1 mutations also becomes significant after a median of 12.9 weeks.
These observations may have important implications for HIV-1 resistance testing. Specifically, Dr Devereux and colleagues suggest that "...HIV-1 resistance testing to direct patients' therapy should only be carried out when on existing therapy, or <2 weeks off therapy, if reliable decisions are to be made relating to further combinations."
Ref: AIDS 1999;13:F123-F127. Source: Reuters Health
|
The ENVA2 trial assessed the performance of laboratories offering genotyping for HIV-1 resistance mutations. The majority of the laboratories had difficulties detecting resistance mutations in a 50:50 mixed sample of wild type and resistant virus. This raises the question as to whether the disappearance of resistance mutations in a genotypic test is identical to a complete disappearance of mutations from that sample. In addition it has been observed in clinical trials that failure of an antiretroviral regimen is associated with the failure of a previous regimen including that drug. This appears to be the case even when a considerable period of time has elapsed between the original and the reintroduced regimens. The observations from this, and Veronica Millers work are interesting and may have practical implications. Despite this work, however, there is no evidence for the complete disappearance of mutant HIV, either from the plasma or archived in resting cells, once it is acquired. Avoidance of drug resistant would still appear of the utmost importance. The utility of treatment breaks may well be accounted for by other reasons than the eradication of drug resistant HIV.
|
Injection drug users and individuals with low educational levels tend to receive highly active antiretroviral therapy (HAART) later in the course of HIV infection compared with other patients, but this delay does not appear to influence the rate of clinical disease progression.
These findings, reported by Dr Matthias Egger of the University of Bristol in the United Kingdom and other members of the Swiss HIV Cohort Study, are published in the December 24th 1999 issue of AIDS.
Dr Egger's group looked at 3342 subjects in this national prospective multicentre study, which included 1007 women. A total of 1155 subjects had acquired the virus through injection drug use and 1172 men became HIV-infected through homosexual contact.
The researchers examined the use of HAART in these subjects, as well as the effect that the timing of treatment had on clinical disease progression. At baseline, the majority of patients (87%) did not have AIDS. The subjects' median CD4 count was 269 cells/µL and their median viral load was 4.3 log10 copies/mL.
After controlling for confounding factors, Dr Eggers' group found that "...the probability of starting HAART was lower in injection drug users compared with men who have sex with men...and in patients with minimum schooling compared with those with vocational training."
However, the researchers found the risk of clinical disease progression to be "...similar among men and women, patients with a history of injection drug use, and patients with lower educational attainment in both univariate and multivariable analysis."
Overall, these "apparently contradictory findings" suggest to the researchers that "...deferring HAART may not be detrimental." However, they stress that confirmation of these data with long-term clinical trials is still needed to determine when HAART should be started.
Ref: AIDS 1999;13:2547-2554. Source: Reuters Health
|
These results encourage deferring antiretroviral treatment to minimise adverse effects such as lipodystrophy syndrome, and to enhance compliance. This study does not, however, inform us any further on when to start therapy. |
Harvey S. Bartnof, MD for hivandhepatitis.com
Two studies published in the January 12th issue of Journal of the American Medical Association address reasons for HIV rebound after HAART (highly active antiretroviral therapy). The U.S. report was presented one year ago at the 6th Conference on Retroviruses and Opportunistic Infections in Chicago. Both studies represented failed attempts at "maintenance therapy" after 3-6 months of "induction" therapy with HAART that included indinavir, zidovudine and 3TC. Maintenance therapy included one, two, or three anti-HIV drugs. Among patients who experienced HIV RNA viral load rebound, researchers attempted to determine the reasons.
The first study was ACTG (AIDS Clinical Trials Group) 343. Patients who achieved viral load undetectability (limit 200 copies per millilitre) after six months of HAART were then randomised into three arms. One was continued triple therapy, while another was ZDV plus 3TC. The third arm was indinavir monotherapy. (Note the virological results of these two major studies reaffirmed the need for ongoing triple drug therapy.)
Results were analysed for those who experienced viral rebound to greater than 200 copies per millilitre during "maintenance" and for those who never achieved viral load undetectability during the 3-drug "induction" phase. Interestingly, in those two groups of 26 patients, the results showed that no primary resistance to indinavir was detected. Both genotypic and phenotypic drug resistance tests were used. (Genotype resistance tests look for gene changes previously associated with resistance to that drug. Phenotype resistance tests attempt to grow the patient's HIV strain with each of the 14 FDA-approved drugs.) The standard M184V resistance mutation to 3TC was found almost universally. (However, 3TC resistance reverses low level resistance to ZDV when the two are combined.) The researchers also measured blood levels of indinavir. There were no overall significant differences in indinavir levels when comparing those with viral rebound (or who never achieved undetectability) to control patients who maintained undetectability. However, the proportion of those with at least one very low level of indinavir was significantly higher among those with rebound than control patients. This suggested that either poor adherence or possibly poor absorption was the reason. (indinavir is not absorbed as well unless taken on an empty stomach or with a low-fat diet.)
In the Trilege Study from France, a 3-month induction phase of the same drugs was used. Then, among those who achieved viral load undetectability (limit 500 copies per millilitre), randomisation to three "maintenance" arms occurred. Those arms were continued triple therapy, ZDV plus 3TC, or ZDV plus indinavir. Among those who had viral rebound greater than 500 copies per millilitre on two occasions, reasons for rebound were investigated.
The results were similar to those in ACTG 343 above. Among those patients with viral rebound, no primary resistance mutations to indinavir were detected. Genotypic drug resistance tests were used. Also, M184V 3TC resistance mutation was common, as expected.
Adherence to therapy in this study was measured by pill counts at clinic visits and blood levels of indinavir. These results showed that those patients with rebound had significantly poorer adherence, as measured by too many left over pills when counted at each visit. Blood level results of indinavir were somewhat different in this study. There was a significantly lower level (subtherapeutic) among those with rebound than among those who sustained viral load undetectability. Yet, indinavir levels were in the therapeutic range among those assigned to indinavir plus ZDV who had only mild viral load rebound.
Both research groups concluded that indinavir resistance may not be the reason for viral rebound (or inability to suppress viral load) in this setting. They also indicated that viral rebound might not be due to resistance to every drug in the regimen-and that one or more drugs could potentially be used in future regimens. In addition, they state that poor adherence (including adhering to dietary restrictions) and suboptimal anti-HIV drug potency might be factors associated with viral rebound or inability to suppress virus.
In the comments section of the ACTG 343 report and in an accompanying editorial by Martin Markowitz, MD, from the Aaron Diamond AIDS Research Institute in New York, other observations were made. Specifically, another reason for rebound, even in the setting of therapeutic drug levels, could be "drug efflux transporters" in cells. These are mechanisms a cell might use to "pump out" a "foreign" drug that it "believes" should not be there. Specific molecules that do just that are "p-glycoprotein transporters" and multiple drug-resistance proteins. (Such transporters are a common mechanism for drug resistance in cancer chemotherapy.) Dr. Markowitz also says that one reason for viral rebound or inability to suppress virus might be different degrees of drug efficacy in and/or penetration of drugs into different body compartments.
These two reports expand our knowledge about the limitations of maintenance therapy in treating HIV disease. In addition, they help to explain why certain anti-HIV drugs are ineffective in achieving or maintaining viral undetectability. Other potential reasons also are addressed. In addition, these studies demonstrate the potential benefits of genotype and phenotype resistance testing and monitoring of drug levels in blood. Lastly, the importance of strict adherence to dosing is underscored.
References: Descamps D and others. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Journal of the American Medical Association 2000 January 12; 283(2): 205-211. http://www.jama.com Havlir DV and others. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. Journal of the American Medical Association 2000 January 12; 283(2): 229-234. http://www.jama.com Markowitz M. Resistance, fitness, adherence, and potency-mapping the paths to virologic failure. Journal of the American Medical Association 2000 January 12; 283(2): 250-251. http://www.jama.com
Source: http://www.hivandhepatitis.com 17/01/00
|
Why should viral load rebound, often to pre-treatment levels after just 3TC failure within a combination? Surely the PI and other NA should still be exerting some pressure, leading to the rapid appearance of resistance to the other components of the regimen. The lack of resistance mutations despite viral rebound suggests a lack of antiretroviral efficacy (drug pressure). An example of this is the original formulation of saquinavir (Invirase) which induced resistance only infrequently. Effective mechanisms lowering the intracellular drug level beginning with poor compliance, low absorption, rapid metabolism and poor influx into or rapid efflux from the cells are possible explanations.
|
Results of a meta-analysis of two randomised controlled HIV treatment trials provide more evidence on the importance of achieving a plasma viral load nadir <20 copies/mL for durable viral suppression. The meta-analysis also supports prior studies showing that baseline viral loads are predictive of the level of suppression that can be achieved and maintained.
According to Dr J. M. Raboud of the Canadian HIV Trials Network in Vancouver, British Columbia, and colleagues, the meta-analysis included the "...original individual patient data from two randomised controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP)."
"The primary purpose of this analysis was to establish whether study subjects with high baseline [plasma viral load] had less of a response to treatment than study subjects with low baseline [plasma viral load]," the researchers explain in the November 1st issue of the Journal of Acquired Immune Deficiency Syndromes.
Dr Raboud and colleagues say that the combined analysis "...extends our earlier results showing that achieving a nadir <20 copies/mL is important for maintaining virologic suppression."
When they included all patients in the analysis, a plasma viral load nadir <20 was 5 times more protective against virologic failure than a plasma viral load nadir between 20 and 400 copies/mL, the group reports.
The analysis also confirms the substantial influence baseline viral loads have on achieving and maintaining suppression. "Baseline [plasma viral load] was a strong predictor of virologic success in both univariate and multivariate logistic [generalized estimating equation] GEE models," the investigators write.
Ref: J Acquir Immune Defic Syndr 1999;22:260-266. Source: Reuters Health
|
An old story but important to re-emphasise. |
Short-term infusion of zidovudine (ZDV) into pregnant rhesus monkeys results in incorporation of the drug into DNA in the placenta as well as in most foetal organs, according to a new report by US government researchers.
These findings suggest that the "...human foetus may also be subject to incorporation of ZDV into DNA...after short-term ZDV infusion to the mother just before delivery," according to Dr Miriam C. Poirier of the National Cancer Institute in Bethesda, MD, and colleagues.
These findings complement those published last year by Dr Poirier's group. As reported by Reuters Health, they found that ZDV was incorporated into the DNA of cord blood leukocytes from 68% of infants exposed to the drug.
To investigate the "genotoxicity of transplacental ZDV exposure," Dr Poirier's group evaluated 4 pregnant rhesus monkeys following continuous infusion with 8 mg ZDV/kg of body weight, which was administered 4 hours before hysterectomy at term.
"This short-term ZDV exposure resulted in ZDV incorporation into DNA of foetal liver, lung, heart, skeletal muscle, brain, testis, and placenta, which varied between 29 and 1944 molecules of ZDV/1 000 000 nucleotides," the researchers report in the December 15th 1999 issue of the Journal of Acquired Immune Deficiency Syndromes.
A fifth monkey received an infusion of 17.3 mg ZDV/kg body weight for about 3 hours, which was stopped 1 hour before hysterectomy. Similar variable levels of ZDV were seen in organ DNA. Most ZDV pharmacokinetic parameters were also comparable to those seen in the other animals and to "...those observed in a similar study of pregnant women."
Dr Poirier's team also found that ZDV values in foetal blood were twofold higher than the levels in maternal blood. In addition, ZDV levels in amniotic fluid were 3-fold higher than those measured in maternal blood.
Overall, there are "...striking similarities in ZDV pharmacokinetics between pregnant rhesus monkeys and pregnant women," as well as genotoxicity in foetal monkeys following short-term ZDV exposure.
Dr Poirier's group therefore recommends that "...children of women receiving ZDV and other nucleoside analogue drugs while pregnant should be carefully observed for potential long-term adverse effects."
Ref: J Acquir Immune Defic Syndr 1999;22:477-483. Source: Reuters Health
|
The relevance of the incorporation of ZDV into foetal DNA may be known perhaps only after decades. A possible oncogenic risk is impossible to exclude to date. However, the proven benefit of ZDV in reducing the rate of HIV-infection of neonates seems to be greater than the possible long-term risk. Incorporation of drug into DNA is likely happening in adults as well as foetuses and with all nucleoside analogues. It would not be a concern with non-nucleoside reverse transcriptase inhibitors such as nevirapine.
|
Research on antiretroviral drugs used to combat HIV-1 recently compared two new regimens of drug treatment containing the nonnucleoside reverse transcriptase inhibitor efavirenz with a drug cocktail made up of zidovudine, lamivudine, and the protease inhibitor indinavir. The study included 450 adults who had not been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor before. The patients were randomly assigned one of three possible regimens: efavirenz plus zidovudine and lamivudine, indinavir plus zidovudine and lamivudine, or efavirenz plus indinavir. Results of the study, which included an average follow-up time of 335 days after treatment started, showed that 49 patients discontinued treatment because of adverse events; 30 of these patients were in the indinavir plus nucleoside reverse-transcriptase inhibitor group. Overall, the scientists found that the combination of efavirenz plus zidovudine and lamivudine had better antiretroviral activity and fewer adverse effects than the indinavir, zidovudine, and lamivudine therapy. The researchers note that the results "strongly support" the use of efavirenz in HIV-1 infected individuals who have not previously been treated.
Ref: Staszewski, Schlomo; Morales-Ramirez, Javier; Tashima, Karen T.; et al. New England Journal of Medicine (16/12/99) Vol. 341, No. 25, P. 1865. Source: CDC HIV/STD/TB Prevention News Update
A recent study involving HIV-1-infected children studied the use of antiretroviral therapy consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors. The 57 young subjects, ages three to 16, were monitored for 48 weeks after therapy began. Before the study started, all but two of the children were receiving one or more nucleoside reverse-transcriptase inhibitors. Two of the most common adverse effects of the treatment were rash, which was reported in 30 percent of the subjects, and diarrhoea, which was reported in 18 percent. Only one child had a life-threatening adverse effect; the child developed neutropaenia with concurrent varicella. Overall, the authors found that combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was tolerated well by the children in the study. The use of such a regimen, which produced "potent and sustained antiviral effects," is an important addition to the antiviral treatments available for HIV-infected children, the researchers.
Ref: Starr, Stuart E.; Fletcher, Courtney V.; Spector, Stephen A.; et al. New England Journal of Medicine (16/12/99) Vol. 341, No. 25, P. 1874. Source: CDC HIV/STD/TB Prevention News Update
|
OPPORTUNISTIC EVENTS
|
The use of Highly Active Antiretroviral Therapy (HAART) has resulted in a lower number of life-threatening infections and deaths due to complications from AIDS. HAART does not, however, appear to have a major impact on HIV-related cancers, particularly non-Hodgkin's lymphoma and cervical cancer.
Many doctors recommend that HIV-positive women have pap smears done on a regular basis, usually every six months. When detected early, treatment for cervical cancer is usually effective. At present, cancerous lesions can be either scraped off or removed by freezing (cryotherapy) or burning (by electric current or laser). In women with HIV, however, the lesions can often reappear after these kinds of treatment.
In an effort to prevent or delay the reappearance of cervical lesions in HIV-positive women, doctors in the United States have been testing an old cancer drug called 5-FU (5-fluorouracil). 5-FU is available in a cream form that can be applied directly to the cervix. The results of a study of 5-FU appeared recently in the Journal of Obstetrics and Gynecology. The 101 women who participated in the study had all previously been treated successfully for cervical cancer. In some women, two grams of 5-FU were applied to the cervix every two weeks for six months. The researchers also monitored the women who did not use the drug during this same period.
The doctors found that the use of 5-FU significantly increased the time it took for new cervical lesions to appear. Moreover, only 28 per cent of women who received 5-FU developed new lesions, compared to 47 per cent of women who did not receive the drug. As with most AIDS-related complications, women with more than 200 CD4+ cells were less likely to develop new lesions than women with fewer than 200 CD4+ cells.
Based on their results, the doctors state that 5-FU offers a "safe and effective" means of delaying the reappearance of cervical lesions in women living with HIV.
Ref: Journal of Obstetrics and Gynecology 1999;94:954-961. Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://http://www.catie.ca"
Two recent reports were published regarding using imiquimod cream for two skin conditions in HIV positive persons. The first is anogenital warts and the second is molluscum contagiosum.
Anogenital Warts
The advent of HAART (highly active antiretroviral therapy) for HIV positive persons has led to an increase in the incidence of skin and oral warts. (The rates have been measured and found to be increased, not simply due to a decrease in many other skin and oral conditions.) Imiquimod (imiquimod 5% cream) is a topical agent approved for the treatment of anogenital warts. Experience using this medication is anecdotal among physicians who have prescribed the medication for their HIV positive patients. Now, researchers from the United Kingdom and the U.S. have published a report indicating that there are some benefits for anogenital warts among HIV positive persons who use topical imiquimod. Warts are caused by the human papilloma virus (HPV), the most common sexually transmitted infection. The study was reported in the journal AIDS in December. The information regarding imiquimod for molluscum is in the second half of this report below.
Imiquimod Cream for Anogenital Warts
Imiquimod is an "immune response modifier," without specific anti-viral properties. It does lead to a local increase in alpha interferon. Whether that response is the mechanism for its benefits in anogenital warts is unknown.
A total of 100 patients (3% women) with HIV infection and anogenital warts were enrolled into the trial. The abstract did not include baseline CD4 counts, HIV RNA viral load levels or current anti-HIV therapy. The study was prospective, randomised, double blind, and "vehicle-" controlled. (Vehicle-controlled means that the "placebo" arm uses the exact formulation of ingredients, except without the active imiquimod medication.) Randomisation was approximately 2:1 for the imiquimod and control arms, respectively. The cream was applied topically on the warts in the genital or anal region for eight hours, three times weekly, up to a maximum of 16 weeks. It is standard for patients using imiquimod to apply the medication before sleep and to wash it off with mild soap and water after the 6-10 hour treatment duration. Hand washing before and after applying the cream also is a standard recommendation. The endpoint in this study was "wart clearance," by measuring the change in height and width of the lesions and also with measurements using pre- and post-photographs.
The results showed that 11% of those who used imiquimod completely cleared their treated warts, compared to only 6% of the control arm. However, these results were not statistically significant. When evaluating the percentage of each arm that had a 50% reduction in their baseline wart area, significantly more patients in the imiquimod arm (38%) achieved that endpoint than in the control arm (14%).
Local side effects were common, yet mild, as occurs among HIV negative persons. Redness (erythema) occurred among 42% of the imiquimod-treated patients and 27% of the placebo patients. The percentage of patients who experienced at least one adverse event was 70% in the imiquimod arm and 66% in the control arm. There were no significant changes in laboratory tests between the treatment and control arms. Other common side effects that occur among HIV negative patients who use imiquimod include localized burning, irritation, itching, pain, rash, soreness, stinging, and tenderness. Some patients who use topical imiquimod can experience mild "flu"-like symptoms, likely due to some absorption of the medication into the bloodstream. Such symptoms include fever, fatigue, headache, and muscle aches.
While the results are not spectacular, there is a clear suggestion of some benefit. It is possible that a longer duration of therapy might increase the response rates.
Toby Maurer, MD, from San Francisco General Hospital (SFGH), has found that topical imiquimod was "most effective in keeping surgically-excised warts [not specifically anogenital] from recurring" among her HIV positive patients taking HAART. Her anecdotal experience (not measuring pre- and post-wart areas with photographs) was that imiquimod "was not that effective" for warts. She did say, however, that skin warts seem to decrease after the CD4 count increases to greater than 400 cells per microlitre as a result of HAART. She added that sometimes, 18 months of HAART might be necessary to achieve a spontaneous decrease in warts. Dr. Maurer is Chief of Dermatology at SFGH and presented an update on skin conditions in HIV/AIDS at the recent 14th Annual Medical Management of AIDS Conference last December in San Francisco.
Imiquimod is rated as Pregnancy Category B. This means that there are no adequate studies in pregnant women and that the drug was not found to induce birth defects in the offspring of rats and rabbits with exposure to the drug during pregnancy.
Molluscum Contagiosum
This is a very bothersome skin condition that occurred among 10-20% of persons with HIV in the pre-HAART era. With widespread use of HAART, molluscum has decreased markedly. However, some HIV positive patients still manifest lesions. This would include those who have low CD4 cell count, because either they are not taking or have had a poor response to HAART. Caused by a pox virus, molluscum manifests as small, flesh-coloured bumps (papules) approximately 2-3 millimetres in diameter. Each one has a central whitish core, usually with an indentation or umbilication. They occur on the trunk, groin and face, particularly on the eyelids. Even though molluscum, by itself, is not dangerous (not life threatening), the cosmetic results are bothersome for many patients. It does not manifest in internal organs of the body.
Particularly among those with a CD4 count less than 50 cells per microlitre, molluscum is very difficult to treat. Each lesion must be treated separately, and new eruptions may occur, due to persistent immune deficiency. Treatment in the past consisted of either cryotherapy (freezing) for each lesion, topical cantharidin treatment for 3-6 hours, or by surgically removing the central core. Now, researchers from Essen and Hamburg in Germany report that another option is topical imiquimod. The letter-to-the-editor was published in the January 4, 2000 issue of Annals of Internal Medicine.
Their open-label study included 15 patients with heavily pretreated molluscum contagiosum. Some of these patients were HIV positive-however, the 15 represented a subset of a larger study and the exact percentage that were HIV positive was not indicated. The mean CD4 count of the HIV positive patients was 323 cells per microlitre. The mean HIV RNA viral load and current anti-HIV therapy were not stated. Prior to enrolment into the current study, the 15 patients had had a mean of 2.7 treatments. The mean duration of molluscum was 9.8 months. The mean baseline lesion area was 210 square millimetres, ranging from 50 to 500 square millimetres. The dosing of imiquimod was not stated; therefore, there is the assumption that standard dosing was used (see Anogenital Warts above.)
The results showed that molluscum was totally cleared in 53% or eight of 15 patients after a mean 9.4 weeks. A 50% reduction of lesion size occurred in another 27% or four patients after a mean of 10.9 weeks. Stable disease (no improvement, not worse) occurred in 13%. One of the 15 patients with a complete response did have a recurrence during a mean follow-up period of 16 weeks. The last or 15th patient either withdrew or was lost to follow-up. Response to imiquimod "did not differ by sex (gender) [or] HIV serostatus."
Side effects were typical, as reported in the first study for anogenital warts above. They included redness, itching, and skin erosion. The complication of a secondary bacterial infection occurred in 9%.
This study did include 50 other patients with refractory skin warts outside of the anogenital region. Some did have HIV infection. However, the percentage with HIV infection was not stated. The mean duration of warts was 29 months, mostly on the hands (40%) or feet (32%). The results were not nearly as impressive as those for molluscum, but were better than those in the first report above for anogenital warts in HIV positive patients. Complete clearance occurred in 30% after a mean 9.4 weeks. A partial response, defined as a 50% reduction in lesion size, occurred in 26%. Stable disease occurred in 22%, while progressive disease occurred in 6%. The other 8 patients or 16% either were lost to follow-up or withdrew due to side effects. As in the molluscum report, the results did not differ by sex (gender) or HIV serostatus.
While there are several limitations to these reports that already were indicated, it does appear that topical imiquimod does have some benefits for HIV positive patients with refractory anogenital warts, molluscum contagiosum, and possibly skin warts outside of the anogenital region. Benefits may require up to four months of treatment to be noticeable-additional benefits after that time are unknown. The recurrence of one case of molluscum after treatment was stopped is noteworthy. That patients can apply the cream on their own is a significant advantage. It should be emphasized that the best treatment of molluscum in HIV positive patients is HAART. Those patients with molluscum who cannot or refuse to take HAART, or who have not responded to HAART, may benefit from topical imiquimod. Lastly, it should be noted that patients with molluscum on the eyelids should have those treated by an ophthalmologist.
References Berger TG. Dermatologic manifestations of molluscum contagiosum. In The AIDS Knowledge Database, Cohen PT and others, editors. Little, Brown and Company, Boston, 5.5-7 to 5.5-8.
Gilson RJC and others. A randomised, controlled safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. AIDS 1999 December, 13(17): 2397-2404.
Hengge UR and Goos M. Topical treatment of warts and mollusca with imiquimod (letter). Annals of Internal Medicine 2000 January 4; 132:94-95.
Maurer T. Dermatological manifestations of HIV: what can the skin tell us about immune reconstitution? Challenges from San Francisco General Hospital. 14th Annual "The Medical Management of AIDS: a Comprehensive Review of HIV Management," sponsored by the University of California at San Francisco School of Medicine and the University of Utah School of Medicine. December 2-4, 1999; San Francisco, California.
Source: http://www.hivandhepatitis.com, 12/01/00.
|
European physicians have observed that the efficacy of imiquimod for anogenital warts is low in patients with low CD4 counts (<200 cells/mm3). Laser treatment or electrotherapy may be the treatment of choice for this group. Mollusca can be removed locally with a "sharp spoon" without scars after local anaesthesia. Imiquimod may be reserved for cases with disseminated mollusca or where local therapy is difficult. |
New research from Australian scientists suggests that granulocyte-macrophage colony-stimulating factor (GM-CSF) may be useful in fighting Mycobacterium avium complex (MAC) infection in patients with HIV. The study, published in the January issue of the Journal of Infectious Diseases (2000;181:390-94), involved the quantification of in vitro phagocytosis activity of monocyte-derived macrophages using a flow cytometric assay. The researchers found that GM-CSF was associated with a reduction of MAC bacteraemia.
Source: CDC HIV/STD/TB Prevention News Update
The percentage of AIDS cases in which non-Hodgkin lymphoma (NHL) is the defining illness has risen in Western European countries since 1995, suggesting that the effects of highly active antiretroviral therapy (HAART) on this complication are less than for other AIDS-defining illness, Italian investigators report.
Dr Silvia Franceschi of the Centro di Riferimento Oncologico in Aviano, and colleagues evaluated AIDS surveillance data from 17 Western European countries. "Between 1988 and 1997, a total of 7148 AIDS cases had NHL as AIDS-defining illness (3.9%)," they report in the November 12th issue of the International Journal of Cancer.
Between 1988 and 1995, the overall number of NHL cases rose steadily, they continue, but began to decline in 1996 and 1997. "As a percentage of AIDS-defining illnesses, however, NHL increased from 3.6% in 1994 to 4.9% in 1997."
Dr Franceschi's group also noted that the risk of AIDS-related NHL appeared to be much lower in developing countries than in developed nations. However, lack of detection and shorter overall AIDS-related survival in developing countries may explain these differences.
Based on these data, they conclude that there has been an increase in AIDS-related NHL in Western Europe since 1995. Therefore, the impact of HAART "...may thus be smaller for NHL than other AIDS-defining illnesses, most notably bacterial and viral infections."
Higher rates of other AIDS-related cancers, such as leukaemia and multiple myeloma, still need to be evaluated.
Ref: Int J Cancer 1999;83:481-485. Source: Reuters Health
Patients with advanced HIV infection may develop massive cutaneous and systemic CD8 T-cell infiltration, a complication that mimics cutaneous T-cell lymphoma (CTCL), but is a consequence of terminal deterioration of the immune system.
Non-Hodgkin lymphomas (NHLs) are a common complication of advanced HIV infection. And although most cases involve B cells, HIV patients may develop CTCL as well, Dr Joan Guitart of Northwestern University Medical School in Chicago, Ill, and associates explain. In some cases, a polyclonal pathogenesis is suspected.
The investigators conducted a retrospective study of HIV-infected patients referred to a dermatology clinic for possible CTCL. Nine patients with atypical T-cell cutaneous infiltrates were identified.
All of these subjects had advanced HIV infection with a "...cutaneous eruption characterized by a dense infiltrate of lymphocytes resembling mycosis fungoides histopathologically, but composed of CD8+ cells," they report in the November issue of the Journal of the American Academy of Dermatology.
Detection of cutaneous CD8+ T-cell infiltrates was associated with a poor patient outcome, with 8 of the 9 patients surviving for less than 1 year. The cause of death in these patients was AIDS wasting or opportunistic infection.
In 6 of the patients who were tested, clonality was not identified, but "...three patients had similar CD8+ infiltrates involving lymph nodes or bone marrow."
Most HIV-related dermatoses involve a CD4 lymphocyte infiltrate, Dr Guitart's group points out, whereas patients with "...HIV-related pseudo-CTCL...tend to have a predominantly CD8 T-cell infiltrate."
Early in HIV infection, CD8 T cells exhibit anti-HIV activity, thereby slowing HIV disease progression. "However, in advanced cases when many cells are infected with HIV, the progressive expansion of cytotoxic T cells...is instrumental in causing immunosuppression."
"This 'betrayal' of the host's immune system with proliferation of reactive CD8 T cells can mimic a neoplastic process," making the correct classification of these cases "difficult and controversial."
Ref: J Am Acad Dermatol 1999;41:722-727. Source: Reuters Health
A new study from researchers at the University of California at San Francisco, suggests that bacterial resistance to trimethoprim-sulfamethoxazole has increased significantly since 1986, especially among HIV-infected individuals. According to the researchers, the prevalence of resistance among Staphylococcus aureus and Enterobacteriaceae genera isolates was under 5.5 percent between 1979 and 1986; however, it soared to 20.4 percent by 1995. Resistance to trimethoprim-sulfamethoxazole among HIV patients was 6.3 percent in 1988 and 53 percent by 1995. The researchers, who report their findings in the December issue of the Journal of Infectious Diseases (1999;180:1809-1818), believe that increased use of the antibiotics caused more resistance.
Source: CDC HIV/STD/TB Prevention News Update
|
Fortunately cotrimoxazole shows no cross-resistance to macrolides, cephalosporins and penicilins. This allows these agents to remain of use when treating respiratory tract, skin and urinary infections. As long as a patient is at risk for PCP the benefit of prophylaxis should outweigh the induction of resistance in these other pathogens. |
|
METABOLIC DISTURBANCES |
Many drugs taken to fight HIV infection can cause an increase in liver enzyme levels. Such increases may be a sign that damage has occurred to the liver. In order to determine which antiretroviral drugs pose the greatest risk of liver toxicity for people with HIV, researchers conducted a study at the John Hopkins University Hospital Clinic in Baltimore. In addition to assessing the risks of liver damage due to antiretrovirals, the researchers sought to establish what role the presence of chronic hepatitis B or C infection plays in the development of liver toxicity. The results of their study appear in the Journal of the American Medical Association.
The team followed 298 patients who received antiretroviral therapies between January 1996 and January 1998. Of that number, 211 were receiving combination therapy including a protease inhibitor (PI). The 87 remaining patients were taking a double combination of nucleoside analogues. In addition to HIV, 52 per cent of subjects in the first group had chronic hepatitis B and C infection. In the double nucleoside group, the corresponding figure was 2.7 per cent.
Severe liver toxicity was observed in 10.4 per cent of the subjects in this study. The highest incidence of severe toxicity was observed in those patients receiving ritonavir (30 per cent). In patients treated with nucleoside analogues alone or with PIs other than ritonavir, the incidence of severe liver toxicity ranged from 5.8 to 6.8 per cent. In patients taking ritonavir, the incidence of severe liver toxicity (30 per cent) was the same among patients with chronic hepatitis C infection (HCV) as among those without. This result seems to suggest that the liver toxicity observed was primarily due to the drug. By contrast, in patients taking nucleoside analogues or PIs other than ritonavir, the incidence of severe toxicity was more than three times that observed in patients without HCV (9.4 per cent versus 2.7 per cent).
Although their data seem to indicate a greater risk of liver toxicity in people with HBV and HCV who take antiretrovirals, the researchers maintain that their results do not support the idea of refusing PI therapy to people with chronic HBV or HCV. Instead, they recommend that further studies be conducted to confirm these results and that patients with HIV-hepatitis co-infection be carefully monitored during treatment.
It is important to note that no deaths or "irreversible outcomes" resulted from the liver toxicity observed in this study.
Ref: JAMA 2000;283(1). The full text of this article is available on the JAMA Web site at http://jama.ama-assn.org/. Source: "From Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://http://www.catie.ca"
|
Commenting on the JAMA article, Abbott (the manufacturer of ritonavir) states " We want to ensure that the HIV Community has accurate information regarding the liver toxicity profile of Norvir and provide you with our clinical experience and perspective in the event you had questions or concerns." "The JAMA article, and some resulting news coverage, points to Norvir (ritonavir) as having a higher incidence of liver toxicity compare with other PIs. The authors site data from 50 Norvir patients of whom 30 percent had grade 3 or 4 transaminase elevations, in a retrospective study of 298 patients." "As you are all aware, Abbott has been monitoring and reporting results of abnormalities in liver function tests associated with Norvir use to regulatory authorities and to the medical community throughout the product's history. Our data of more than 900 patients in three controlled clinical studies demonstrated the overall incidence of severe hepatotoxicity with Norvir, using similar criteria as the JAMA article, is consistently in the range of 5 - 10 percent. In addition, we have observed in these studies that this incidence is increased in patients with underlying liver disease, such as HCV or HBV, and proactively notified the FDA in November 1996, which resulted in labeling reflecting these observations." "Additionally, in at least one other controlled study comparing ritonavir, indinavir and ritonavir/saquinavir published by Dr. Kirk, et al (AIDS 1999, 13:F9-F16) and not sponsored by Abbott, there was even a lower incidence of severe hepatotoxicity than the aforementioned 5-10 percent range, and the incidence in patients treated with ritonavir or ritonavir/saquinavir had a lower rate of elevated liver function tests compared to indinavir." "The study referred to in the JAMA article was a prospective chart review from 1996 - 1998 -- a look at the charts of people being treated at one center. We believe the patient population was not representative of the general HIV population, primarily because they came from only one institution, and because the proportion of patients with underlying hepatitis (B or C) was higher than that of the general population of HIV-infected patients. In addition, of the 298 patients, only 50 were taking ritonavir. We don't know from the study very much about patient health, nor do we know what dose the Norvir patients were taking (Norvir was taken primarily at the 600 mg BID dose when first approved and is now more commonly used at 400 mg BID), or what other drugs were being used in combination with Norvir (or the other antiretrovirals in the study). Little information is provided on the presence or absence of side effects associated with the liver test abnormalities." "While we do not want to minimize the risk for liver function abnormalities from Norvir use, especially for those who have underlying hepatitis, we do want to ensure the HIV community -- and patients across the country -- have accurate information in hand when reviewing the JAMA article or the resulting publicity." |
Angiolipomas may represent another complication of protease inhibitor therapy, according to physicians at the University of Washington-Harborview Medical Center in Seattle.
A lipodystrophy syndrome, characterized by peripheral lipoatrophy and central adiposity, as well as hyperlipidaemia and insulin resistance, develops in many HIV-infected patients treated with protease inhibitors.
Drs Jan P. Dank and Roy Colven now describe 3 HIV-infected patients who developed symptomatic angiolipomas after starting protease inhibitor therapy. All of the subjects were treated with indinavir and 1 patient also received saquinavir and nelfinavir.
In all 3 patients, "...the symptomatic appearance of the lesions followed the initiation of protease inhibitors by many months," the investigators report in the January issue of the Journal of the American Academy of Dermatology. "This time course is similar to that reported for the appearance of central fat redistribution after beginning protease inhibitors."
One patient had at least 1 pre-existing subcutaneous lesion. However, the lesion grew in size and became painful only after protease inhibitor therapy was administered.
"Although an association based on a limited number of case reports must be treated with caution," the physicians believe that "...the temporal association in the cases reported makes the association plausible."
Confirmation of this association would make angiolipomas a new minor protease inhibitor complication and may also provide "...a potential model for studying the mechanism of the lipodystrophy syndrome itself."
Ref: J Am Acad Dermatol 2000;42:129-131. Source: Reuters Health
|
IMMUNOLOGY AND IMMUNOTHERAPY
|
Abstract
Human immunodeficiency virus (HIV) infection is associated with progressive loss of circulating CD4+ lymphocytes. Treatment with highly active antiretroviral therapy (HAART) has led to increases in CD4+ T lymphocytes of naive (CD45RA+62L+) and memory (CD45R0+RA-) phenotypes. Thymic computerized tomography scans were obtained on 30 individuals with HIV disease to investigate the role of the thymus in cellular restoration after 48 weeks of HAART. Individuals with abundant thymic tissue had higher naive CD4+ T lymphocyte counts at weeks 224 after therapy than individuals with minimal thymic tissue.
Individuals with abundant thymic tissue had significantly larger increases in naive CD4+ cells during the first 4 weeks of therapy. These individuals were also more likely to experience viral rebound despite comparable initial declines in plasma HIV-1 RNA.
These findings suggest that there is a complex relationship among the thymus, viral replication, and lymphocyte restoration after application of HAART in HIV disease.
Ref: Kimberly Y, Smith H, Valdez A et al. The Journal of Infectious Diseases 2000;181:141-147. Full text: http://http://www.journals.uchicago.edu/JID/journal/issues/v181n1/990232/990232.html
Researchers, led by Dr. Ana Puri of the National Cancer Institute, have found that influenza infection raises the susceptibility of cells to infection by HIV-1 isolates that use the CXCR4 coreceptor. The team, which reported its findings in the January 1 issue of AIDS Research and Human Retroviruses (2000;16:19-25), conducted an in vitro study to determine the impact of the influenza strain A/PR/8 on HIV-1's replicative ability. The researchers conclude that the influenza virus increases CXCR4 expression and thus influences HIV-1 infection.
Source: CDC HIV/STD/TB Prevention News Update
|
A clinical trial showing a detrimental effect of influenza vaccination on the course of HIV-infection is lacking. Retrospectively analysing the MACS, EUROSIDA or Swiss cohorts might be a possible way to tackle this problem. |
|
OTHER NEWS
|
The European AIDS Treatment Group starts a campaign to facilitate an earlier access to anti-HIV products for patients in desperate need: The European legislation needs to be amended for the European Medicinal Evaluation Agency to be able to represent 15 EU Member States when negotiating early access programs with the pharmaceutical industry.
An EATG delegation met with the Committee for Proprietary Medicinal Products (CPMP) at the EMEA in London on the 14th December 1999. The CPMP is the committee of experts which evaluates, approves or rejects new drug applications for all medicinal products which target the EU market. Since 1995, all new anti HIV products available in Europe have been approved through this centralised procedure.
The EATG presented the time-gaps in access to promising anti HIV products which still exist between HIV patients in Europe and in the US. An EATG survey revealed these gaps by presenting data from recent early access programs. These programs are aimed at people who have failed all other products and who are at high risk to develop AIDS or to die (compassionate access programs):
| New product | Delay between the first patient treated in an early access program in the US and in the EU |
| 1995: saquinavir (Invirase®) | 90 to 120 days |
| 1997: Nelfinavir (Viracept ®) | 210 days between the US and France, 420 days for the rest of the EU |
| 1998: Abacavir (Ziagen®) | 150 to 900 days |
| 1999: Amprenavir (Agenerase ®) | 60 to 390 days |
| 1999: Adefovir (Preveon®) | 450 days (only 1 EU state) |
| 1999: Norvir® new capsule | 30 days to > 180 |
| 1999: Lopinavir ABT378/r | 30 days to > 150 |
| 2000: Tenofovir PMPA | > 180 days |
"This situation will not change unless Europe adopts legislation where a single institution like the EMEA can be the unique interlocutor to conduct negotiations with the industry. One single and strong European voice has more chances to be heard clearly than 15 different ones", stated Franois HouĜez, France, leader of the EATG delegation. "The difficulties we are facing entering 2000 is that despite encouraging trials results, the industry does not have enough product to fill the needs of patients" Simon Collins, EATG, UK, explained. "As long as Industry waits for phase III results to be out to decide to increase production, we will always be facing a situation where a few hundred people will be enrolled in US early access programs through a Treatment IND status by the Food and Drug Administration and European people will have to wait years after".
According to members of the CPMP and to a representative of the European Commission, one possible solution could be to grant conditional approval after phase II results (when the safety of a new product is known as well as some efficacy data), instead of at the end of phase III, allowing the industry to anticipate the production of commercial batches.
Ariel North of the European Commission said that this could make a difference of years in getting access to new compounds, going through a revised "conditional marketing authorisation" or a "harmonised" compassionate use". This conditional approval would be a signal to Industry that indeed Europe is willing to negotiate the definition of "exceptional circumstances". According to Chairman Prof. Alexandre, the CPMP is "capable and ready to do a lot in this area, and on the national level we can do everything except supply drug".
This would change the heterogeneous situation in Europe regarding early access programs and be an initiative to resolve this inequity.
Within European countries, early access programs rely on national rules which vary greatly from one country to another. Nikos Dedes, EATG, Greece: "The result is a nightmare: any pharmaceutical company that wishes to make a new product available to patients who have exhausted all other anti-HIV products has to deal with 15 different legislations. This results in extra delays and forces people to travel to other states where they can purchase the new product or pay very expensive and sometimes illegal parallel imports. In some countries, such compassionate programs are so difficult to put in place that they may never happen. During the pricing negotiations that follows approval, the newly approved product is still not on the market. And such negotiations can last over the 90 legal days".
According to the EATG, there are special advantages of a system of conditional approval:
About the EATG
The European AIDS Treatment Group is the first and only pan European AIDS Treatment advocacy group. Founded seven years ago the EATG has currently more than 100 members from over 20 European countries. The EATG is a charity organisation under German law and has its headquarters in Dsseldorf, Germany.
Address:
EATG, Mindener strasse 33,
40227 Dsseldorf,
Germany
tel +49 211 7883481, fax: +49 211 7885414,
email: office@eatg.org
The Treatments Policy Forum will be holding an election in early February to elect one community representative to sit on the British HIV Association (BHIVA) executive. The representative will be one of two sitting on the executive and will serve a term of 2 years. Applicants must;
For an application pack or more information please contact Saul Walker at the National AIDS Trust on 020 78 14 67 31 or saul.walker@nat.org.uk Completed application forms must be returned by 28 January 2000.