Contents
- Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers
- Higher plasma concentrations of protease inhibitors speed HIV load decline
- Resistance-associated loss of viral fitness in human immunodeficiency virus type 1
- Efavirenz use in Children
- Five drug antiretroviral combination gives improved initial suppression of viral load
- Low dihydrotestosterone and weight loss in the AIDS wasting syndrome
- Transdermal testosterone use in women with AIDS wasting
- Effects of androgen administration in men with the AIDS wasting syndrome
- Testosterone may relieve fatigue in HIV-positive men
- Exercise as a mediator of psychological and nutritional effects of testosterone therapy in HIV+ men
- Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines
- HIV Vpr immune effects
- Immune markers have additional prognostic value in HIV infection
- Epstein-Barr virus and lymphoma of the CNS
- HIV-positive patients and cardiac disease
- ON THE WEB
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Antiretroviral Drugs and Treatment Strategies
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Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers
The potential pharmacokinetic drug-drug interaction between delavirdine, a non-nucleoside analogue reverse transcriptase inhibitor, and indinavir, an inhibitor of HIV protease was evaluated in healthy volunteers. Subjects received a single 800-mg dose of indinavir sulphate on day 1 (baseline). Delavirdine mesylate 400 mg was administered three times daily on days 2 through 10. On day 9, a single 400-mg dose and on day 10 a single 600-mg dose of indinavir were given along with morning doses of delavirdine. Pharmacokinetic evaluations of indinavir were made on days 1, 9, and 10, and of delavirdine on days 8, 9, and 10. Fourteen healthy male volunteers completed the study. Single doses of indinavir had no clinically important effects on the pharmacokinetics of delavirdine. Mean indinavir Cmax values for the 400-mg and 600-mg doses administered concomitantly with delavirdine were dose proportionally lower than that observed following the 800-mg dose administered alone. Mean Tmax values were similar and ranged from 1.0 +/- 0.3/hour for indinavir 800 mg administered alone to 1.3 +/- 0.4/hour for indinavir 600 mg administered with delavirdine. These results indicate that delavirdine had no clinically important effect on the rate of indinavir absorption. In contrast, the mean indinavir AUC0-infinity, value following the 400-mg dose administered with delavirdine was only 14% lower than the baseline value determined for the 800-mg indinavir dose (25,400 +/- 6960 nM hour versus 29,600 +/- 7920 nM hour), and the mean indinavir AUC0-infinity value for the 600-mg indinavir dose administered with delavirdine (42,700 +/- 9800 nM hour) was 44% greater than the baseline value. All differences among mean AUC0-infinity values were statistically significant. Mean indinavir half-life values were slightly longer when indinavir was given in a dose with delavirdine than when indinavir was administered alone. These results suggest that delavirdine inhibits metabolism of indinavir and support the possibility of a reduction in the magnitude or frequency of indinavir dosage when given in combination with delavirdine. Ref: Ferry JJ, Herman BD, Carel BJ, Carlson GF, Batts DH. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1;18(3):252-259
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Multi-nucleoside resistance in those with long histories of incomplete suppression of viral replication while taking this class of drugs (most mono and dual NA recipients) has increased interest in combination therapy NOT including nucleoside analogues. Durable, potent effects have been observed with indinavir + efavirenz. However both efavirenz and nevirapine induce CYP3A4 leading to reductions in PI exposure and the consequent need for higher PI doses. Delavirdine has the advantage of being an inhibitor of CYP3A4 which generally leads to increased PI exposures (as seen in the DLV/IND interaction study outlined above). BID dosing and pills containing higher amounts of delavirdine are being developed so BID regimens with DLV + one or two PI's represent potentially useful, patient friendly NNRTI-PI regimens of the future. Efficacy data and three-way PK interaction studies (DLV + double PI's) are now needed. Uncontrolled data on adding DLV to a failing combination of IND/ZDV/3TC was reported by Bellman at last years ICAAC meeting [abs. I-170] and on the combination of 2 PI's (NFV + IND), DLV and NA's at Geneva (abs. 12275, see Dr Fax issue 51). |
Higher plasma concentrations of protease inhibitors speed HIV load decline
Higher levels of exposure to protease inhibitors correlate with a higher initial clearance rate of plasma HIV-1 RNA in antiretroviral-naive HIV-1-positive patients, according to a new report by Dutch researchers.
Several mathematical models, which have been used to describe HIV-1 replication in vivo, have assumed full or constant inhibition of viral replication on exposure to antiretroviral drugs, Dr. Richard M.W. Hoetelmans of Slotervaart Hospital in Amsterdam and colleagues explain. "However," they point out, "...interindividual variability in exposure to antiretroviral drugs is large."
In the current study, which appears in the July 30th issue of AIDS, they compared the initial rate of plasma HIV-1 RNA clearance with exposure to antiretroviral drugs. Participants were members of the Amsterdam Duration of Antiretroviral Medication (ADAM) study who received induction therapy with a 4-drug regimen containing the protease inhibitors nelfinavir and saquinavir, along with stavudine and lamivudine. This was followed by a 2-drug maintenance regimen.
During the first 8 weeks of treatment, Dr. Hoetelmans' group measured plasma concentrations of nelfinavir and saquinavir in 34 patients. They were able to determine the elimination rate constant (k) for HIV-1 RNA clearance in 29 patients during the first 2 weeks of treatment.
The researchers observed a variation in the elimination rate constant of approximately 4-fold among the subjects. And the results of univariate analysis indicated a "significant positive correlation" between k and the median concentration ratios of nelfinavir or saquinavir. "In multivariate analyses, the median [nelfinavir] concentration ratio remained significantly correlated with k," they report.
"The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to [nelfinavir] and [saquinavir]," they conclude.
Based on these findings, Dr. Hoetelmans' group believes that "...k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increased doses of drugs administered in combination regimens." Ref: AIDS 1998;12:F111-F115. Source: CDC Daily News Update
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This study addresses two issues. Firstly, can therapeutic drug monitoring help select patients who may benefit from upward adjustments in PI dosing? - the answer appears to be yes (probably), although in vivo efficacy thresholds are difficult to determine. Secondly, can establishment of antiviral efficacy during drug development be aided by very short term data, alleviating the need for prolonged potentially suboptimal dosing as is currently employed in dose-finding studies of new antiretrovirals? - an intriguing possibility worthy of further evaluation.
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Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients.
Abstract We have studied the phenotypic impact of adaptive Gag cleavage site mutations in patient-derived human immunodeficiency virus type 1 (HIV-1) variants having developed resistance to the protease inhibitor ritonavir or saquinavir. We found that Gag mutations occurred in a minority of resistant viruses, regardless of the duration of the treatment and of the protease mutation profile. Gag mutations exerted only a partial corrective effect on resistance-associated loss of viral fitness. Reconstructed viruses with resistant proteases displayed multiple Gag cleavage defects, and in spite of Gag adaptation, several of these defects remained, explaining the limited corrective effect of cleavage site mutations on fitness. Our data provide clear evidence of the interplay between resistance and fitness in HIV-1 evolution in patients treated with protease inhibitors. Ref: Mammano F, Petit C, Clavel F. J Virol 1998 Sep;72(9):7632-7637
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Data presented at the Lake Maggiore meeting by Brendan Larder (abs. 23) showed a prevalence rate of 27% (82/300) for detection of gag mutations in PI resistant HIV-1. Their group found an association between the A431V (p7/p1 P2 position) gag mutation and the codon 82 protease mutation and between the L449F (p1/p6 P1' position) gag mutation and the codon 84 protease mutation. Data also suggested that there might be selection against these gag site changes in replication competent, PI resistant viruses, perhaps reflecting the loss of fitness of gag mutated virus seen in the above study. Current genotyping tests do not routinely look for gag cleavage site mutations. |
Efavirenz use in Children
Efavirenz (SustivaTM, formerly DMP-266) is a new drug in the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Other drugs in this class are nevirapine and delavirdine. Efavirenz is not licensed for marketing in Europe but is available in compassionate use expanded access programmes or on a named patient basis.
Some physicians have expressed an interest in the use and availability of efavirenz for children with HIV-disease and data on it's use in this patient group are expected to be presented at the up-coming ICAAC conference in San Diego (24th-27th September 1998). Efavirenz is available in the UK for paediatric use on a named patient basis with similar programmes becoming established in Europe.
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There is currently little experience on potential CNS effects of efavirenz in children so no specific recommendations can be made at this time. Dose reduction and dose splitting are no longer suggested as strategies to manage side effects as these adjustments have no discernible effect and in the case of dose reduction may increase the risk of resistant HIV emerging. UK physicians should direct inquiries on paediatric use and potential or observed adverse effects to Dr. Kitty Smith at Du Pont Pharma, Tel: 01462 488265, Fax: 01462 488294. Reports from the 38th Annual ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy) Conference are scheduled for inclusion in Issue 55 of AIDS Treatment Projects "Doctor Fax" to be distributed in early October. |
Five drug antiretroviral combination gives improved initial suppression of viral load
HIV-1 RNA load can be suppressed to below detectable levels (50 copies per millilitre) more rapidly using a five-drug combination regimen than using a three-drug antiretroviral regimen, which is considered the standard of care, according to Dutch researchers.
[The abstract of this report was first published as a "fast tracked" article in the journal AIDS and reproduced in ATP's Doctor Fax issue 45 - see "5-drug regimen provides improved initial suppression of HIV-1 replication over triple therapy"]
In a preliminary report, Dr. Joep M. A. Lange of the University of Amsterdam and colleagues compared the efficacy of a three-drug regimen in 15 subjects with the efficacy of a five-drug regimen in 9 subjects. All participants had HIV-1 RNA levels of 10,000 copies per millilitre or more at baseline.
Dr. Lange's findings, which include data at 12 weeks, appear in the July 30th issue of AIDS.
Patients on the three-drug regimen received two nucleoside analogues (zidovudine and lamivudine) and a protease inhibitor (ritonavir). Patients on the five-drug regimen, eight of whom were antiretroviral naive, received zidovudine, 3TC, abacavir, indinavir and nevirapine. The ninth subject received a comparable five-drug combination, but instead of zidovudine and 3TC, stavudine and ddI were administered.
Dr. Lange's team found that viral suppression to less than 50 copies per millilitre was reached by a median of 4 weeks among patients on the five-drug regimen, while those on the three-drug regimen took a median of 12 weeks to reach this level.
They suggest that this more rapid decline in viral load "...will translate into more durable suppression of viral replication." And this may also be "...of particular relevance to patients with a very high plasma viral load who initiate antiretroviral therapy."
The investigators suspect that the findings would also be applicable in protocols involving induction therapy followed by maintenance therapy. "One would not like to conclude wrongly that a maintenance therapy will not work because a suboptimal viral regimen was used in the induction phase," they explain.
Dr. Lange's group concludes that triple-drug treatment does not "...represent the zenith of anti-HIV activity."
Ref: AIDS 1998;12:F117-F122. Source: CDC Daily News Update
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Although triple drug combinations may not represent the zenith of antiretroviral activity they appear to be adequate in maintaining suppression of viral replication below quantifiable limits in 40 - 60% of antiretroviral naive patients even over the longer term (Mercks 035 study data on IND/ZDV/3TC recipients and the INCAS study data on NVP triple based combinations). Treating such fortunate people with more than 3-drug combinations seems not to be necessary. Alternative strategies have to be developed and validated to address the 60 - 40% who may need more potent therapy. Can they be identified before initiating therapy (high baseline viral load, low CD4, length of time HIV-infected)? Or would intensification strategies if slope of viral decay in initial 4 weeks was unimpressive work? Of course more drugs = more interactions, potential for more side-effects and higher costs, but then so, usually, does failure of the initial regimen. With increased experience with BID dosing of double PI based combinations and triple class combinations (PI + NNRTI + NA's) more components does not have to mean harder compliance, especially when patients understand the necessity of driving viral load as low as possible to ensure some longer term durability. |
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ENDOCRINOLOGY
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Low dihydrotestosterone and weight loss in the AIDS wasting syndrome.
Abstract
24 consecutive AIDS patients with wasting, and who had never received anabolic therapies, were evaluated to determine their profile of sex hormones and whether transformation of testosterone (T) to the nuclear androgen, dihydrotestosterone (DHT), was impaired. Eleven (46%) patients had normal testosterone and DHT (group I), 10 (42%) had normal testosterone but low DHT (group II), and 3 (12%) had low testosterone and low DHT (group III). Age, prior opportunistic complications, symptoms, serum albumin, haemoglobin levels, and CD4 lymphocyte counts were similar in the groups. DHT was significantly lower (22.2 +/- 6.8 microg/dl) in group II compared with group I (50.8 +/- 15.3 microg/dl). The ratio of T/DHT, a measure of the conversion of testosterone to DHT, in group I was 15.1 +/- 3.5, which was within the range for eugonadal young men. In group II, the ratio was 22.3 +/- 1.5, indicating a defect in generation of DHT. Patients in group II had lost 9.2 +/- 3.5 kg compared with 5.6 +/- 2.6 kg in group I (p = .015). Thus, a syndrome of low DHT with normal testosterone was associated with significantly greater weight loss than in patients with normal testosterone and DHT. Further studies are needed to clarify whether low DHT is a result of AIDS wasting or is causally related to weight loss and whether androgen therapy in the form of DHT could reverse some of the metabolic changes associated with AIDS wasting.
Ref: Sattler F, Briggs W, Antonipillai I, Allen J, Horton R. J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1;18(3):246-251
Transdermal testosterone use in women with AIDS wasting
The results of a pilot study indicate that transdermal administration of testosterone in women with AIDS wasting is safe and well-tolerated. Also, a multicenter team of investigators reports, testosterone administration is associated with weight gain and improved quality of life.
Dr. Steven Grinspoon of the Massachusetts General Hospital and colleagues report on this preliminary investigation of testosterone administration in women with AIDS wasting in the August issue of the Journal of Clinical Endocrinology and Metabolism.
In the current study, they identified 53 women with AIDS who weighed less than 90% of their ideal body weight or had lost more than 10% of their body weight since the onset of their illness. The women were then randomised into one of three groups: two active testosterone patches, one active and one placebo patch, or two placebo patches.
The expected normal delivery rate for the two active patches was 300 µg/day, and 150 µg/day for the one active and one placebo patch. The transdermal patches were applied two times a week for 12 weeks.
Dr. Grinspoon's group observed a significant weight gain (1.9 kg) in the subjects treated with one active and one placebo patch, compared with the subjects who received placebo only (0.6 kg). However, there were no significant increases in weight gain among the women who received the higher dose administered through the two active patches. There was also a significant suggestion that weight gain was associated with an improved quality of life.
Ref: J Clin Endocrinol Metab 1998;83:2717-2724. Source: JAMA HIV/AIDS Information Centre
Effects of androgen administration in men with the AIDS wasting syndrome. A randomised, double-blind, placebo-controlled trial.
Abstract
BACKGROUND: Development of successful anabolic strategies to reverse the loss of lean body mass is of critical importance to increase survival in men with the AIDS wasting syndrome. Hypogonadism, an acquired endocrine deficiency state characterised by loss of testosterone, occurs in more than half of all men with advanced HIV disease. It is unknown whether testosterone deficiency contributes to the profound catabolic state and loss of lean body mass associated with the AIDS wasting syndrome.
OBJECTIVE: To investigate the effects of physiologic testosterone administration on body composition, exercise functional capacity, and quality of life in androgen-deficient men with the AIDS wasting syndrome.
DESIGN: Randomised, double-blind, placebo-controlled study.
SETTING: University medical centre.
PATIENTS: 51 HIV-positive men (age 42 +/- 8 years) with wasting (body weight <90% of ideal body weight or weight loss >10% of baseline weight) and a free testosterone level less than 42 pmol/L (normal range for men 18 to 49 years of age, 42 to 121 pmol/L [12.0 to 35.0 pg/mL]).
INTERVENTION: Patients were randomly assigned to receive testosterone enanthate, 300 mg, or placebo intramuscularly every 3 weeks for 6 months.
MEASUREMENTS: Change in fat-free mass was the primary end point. Secondary clinical end points were weight, lean body mass, muscle mass, exercise functional capacity, and change in perceived quality of life. Virologic variables were assessed by CD4 count and viral load.
RESULTS: Compared with patients who received placebo, testosterone-treated patients gained fat-free mass (-0.6 kg and 2.0 kg; P = 0.036), lean body mass (0.0 kg and 1.9 kg; P = 0.041), and muscle mass (-0.8 kg and 2.4 kg; P = 0.005). The changes in weight, fat mass, total-body water content, and exercise functional capacity did not significantly differ between the groups. Patients who received testosterone reported benefit from the treatment (P = 0.036), feeling better (P = 0.033), improved quality of life (P = 0.040), and improved appearance (P = 0.021). Testosterone was well tolerated in all patients.
CONCLUSIONS: Physiologic testosterone administration increases lean body mass and improves quality of life among androgen-deficient men with the AIDS wasting syndrome.
Ref: Grinspoon S, Corcoran C, Askari H et al. Ann Intern Med 1998 Jul 1;129(1):18-26.
Testosterone may relieve fatigue in HIV-positive men
About 80% of symptomatic HIV-infected men with clinical hypogonadism respond well to testosterone therapy, according to a New York team of investigators.
This and other findings, from a 12-week open trial conducted by Dr. Glenn J. Wagner of the New York State Psychiatric Institute in Manhattan and colleagues, appear in the August 15th issue of General Hospital Psychiatry.
Dr. Wagner's team enrolled 73 HIV-positive men, 72% of whom had an AIDS diagnosis, in the trial. All the subjects had clinical hypogonadism and correlates of fatigue, which "...included elevated laboratory values (haematocrit, haemoglobin), lower overall physical functioning, greater psychological distress, and reduced quality of life," they write.
The subjects were first given 200 mg of testosterone injected biweekly, which was increased to 400 mg after 2 weeks. Dr. Wagner's team found that of the 66 men who completed the trial, 52 subjects, or 79%, had improved energy levels. Treatment was also well-tolerated.
Ref: Gen Hosp Psychiatry 1998;20:209-213. Source: CDC Daily News Summaries
Exercise as a mediator of psychological and nutritional effects of testosterone therapy in HIV+ men
Abstract
PURPOSE: The purpose of this study was to determine whether exercise mediates the psychological and nutritional effects of testosterone therapy in men with symptomatic HIV illness, low serum testosterone, and clinical symptoms of hypogonadism.
MAETHODS: A 12-wk open trial of biweekly intramuscular testosterone injections was conducted, with 54 men completing the trial and exercise assessments. Most (71%) men were diagnosed with AIDS; 41% had a CD4 < 50. One-third of the men were diagnosed with major depression, and nearly half had some evidence of wasting. Twenty-nine men (54%) engaged in exercise (predominantly resistance training) during the trial. Exercisers did not differ from non-exercisers on any measure of psychological well being or nutritional status at baseline.
RESULTS: After 12 wk of testosterone treatment, those who exercised showed significant improvement in mood (Hamilton Rating Scale for Depression; HAM-D) and overall distress (Brief Symptom Inventory; BSI) (P < 0.000 for both), as well as a significant increase in body cell mass (P < 0.01) and lean body mass (mean increase of 2.6 kg; P < 0.000) as measured by bioelectric impedance analysis. In contrast, non-exercisers showed improvement on the HAM-D (P < 0.000), but not the BSI or measures of nutritional status.
CONCLUSION: These findings indicate that exercise may be an important adjunct to testosterone therapy in the treatment of psychological distress and wasting symptoms in men with symptomatic HIV illness.
Ref: Wagner G., Rabkin J., Rabkin R. Med.Sci.Sports Exerc, 30 (6):811-817 (1998 Jun).
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DHT is not routinely measured in clinical assays of testosterone levels (free testosterone only is normally measured). Low testosterone also appears to be more common in patients with lipodystrophy on PI's perhaps in part because PI's may block conversion of testosterone to DHT. These studies, focusing on later stage patients with wasting, suggest supplementation with modest amounts of testosterone can increase lean body mass. It's use is also often associated with increased energy, libido and sense of well-being. |
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PATHOGENESIS
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Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro
Abstract Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normal T cell expressed and secreted), which are the natural ligands of the CC-chemokine receptor CCR5, inhibit replication of MT-2- negative strains of HIV-1 by interfering with the ability of these strains to utilise CCR5 as a coreceptor for entry in CD4(+) cells. The present study investigates the capacity of natural killer (NK) cells isolated from HIV-infected individuals to produce CC-chemokines and to suppress HIV replication in autologous, endogenously infected cells as well as to block entry of MT-2-negative HIV into the CD4(+) T cell line PM-1. NK cells freshly isolated from HIV-infected individuals had a high number of mRNA copies for MIP-1alpha and RANTES. NK cells produced significant amounts of RANTES, MIP-1alpha, and MIP-1beta constitutively, in response to stimulation with IL-2 alone and when they were performing their characteristic lytic activity (K562 killing). After CD16 cross-linking and stimulation with IL-2 or IL-15 NK cells produced CC-chemokines to levels comparable to those produced by anti-CD3-stimulated CD8(+) T cells. Furthermore, CD16 cross-linked NK cells suppressed (49-97%) viral replication in co-cultures of autologous CD8/NK-depleted PBMC to a degree similar to that of PHA or anti-CD3-stimulated CD8(+) T cells. In 50% of patients tested, NK-mediated HIV suppression could be abrogated by neutralising antibodies to MIP-1alpha, MIP-1beta and RANTES; in contrast, CD8(+) T cell-mediated suppression was not significantly overcome upon neutralisation of CC-chemokines. Supernatants derived from cultures of CD16 cross-linked NK cells stimulated with IL-2 or IL-15 dramatically inhibited entry of a MT-2-negative strain of HIV, BaL, in the CD4(+)CCR5(+) PM-1 T cell line. These data suggest that activated NK cells may be an important source of CC-chemokines in vivo and may suppress HIV replication by CC-chemokine-mediated mechanisms in addition to classic NK-mediated lytic mechanisms.
Ref: Oliva A, Kinter AL, Vaccarezza M et al. J Clin Invest 1998 Jul 1;102(1):223-231.
HIV Vpr immune effects
According to research by Irvin Chen of the University of California-Los Angeles School of Medicine and colleagues, HIV that was assumed harmless and inactive after highly active retroviral therapy may still be harmful to the immune system by producing a viral protein, Vpr, which kills immune cells. In the journal Science, Chen noted that the researchers were surprised to find that the Vpr protein was still active, halting the cell cycle and ultimately causing apoptosis. Additionally, the virus does not have to replicate for Vpr to take effect. The findings could explain why recovery takes such a long time, even when patients have been taking the drugs for an extended period and have been symptom free.
Ref: Science. Vol. 281, 5374, 266-269. (10.07.98) Source: CDC Daily News Update
Immune markers have additional prognostic value in HIV infection
Although HIV RNA levels in early infection are important in assessing long-term prognosis, immune activation markers also provide meaningful prognostic information, according to UK researchers.
Dr. Caroline A. Sabin of the Royal Free Hospital of Medicine in London and colleagues assessed measures of immune response, including CD4+ and CD8+ T cell counts, and IgA and IgG, along with HIV RNA values in 97 men with haemophilia.
The researchers evaluated HIV RNA levels about 2.5 years following seroconversion, and immune markers were assessed within 1 year of viral load determinations. Dr. Sabin's team monitored the subjects for up to 17 years. Their findings appear in the July 30th issue of AIDS.
As previously reported by others, they found high HIV RNA levels to be predictive of rapid progression to AIDS and death. However, Dr. Sabin's team also noted that high levels of IgA and IgG measured at about the same time provided "...comparably powerful independent prognostic information for AIDS and death."
These observations suggest "...that the immune activation itself, rather than merely an association with HIV RNA levels, is an additional contributing factor to subsequent disease progression."
Ref: AIDS 1998;12:1347-1352. Source: CDC Daily News Update
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OPPORTUNISTIC EVENTS
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Epstein-Barr virus and lymphoma of the CNS
CNS lymphoma (central nervous system) is a life-threatening cancer that affects some people living with AIDS. Like most cancers, lymphoma is treated with combination chemotherapy, and responds best to treatment if detected early. According to researchers in the UK, one key to early detection of CNS lymphoma may lie in the presence of Epstein-Barr virus DNA in the cerebrospinal fluid (CSF) of patients with HIV.
Dr. N. S. Brink and colleagues at the University College London Hospitals tested the CSF of 115 HIV+ individuals for the presence of Epstein-Barr virus (EBV) DNA, as well as Kaposi's sarcoma-related herpesvirus DNA. They found that EBV DNA was present in every patient with primary CNS lymphoma or both CNS and systemic lymphoma (spread throughout body). The doctors also report that EBV DNA was found in 9 other patients in whom lymphoma had not been diagnosed at the time of testing, 2 of whom went on to develop it later. It should be noted, however, that 2 patients whose CSF had shown no sign of EBV DNA went on to develop CNS lymphoma as well. Interestingly, no viral DNA was detected in patients with systemic lymphoma, but not CNS lymphoma. In light of their findings, the researchers conclude that "detection of EBV DNA in the CSF of patients with HIV is strongly associated with primary CNS lymphoma as well as cerebral involvement from disseminated systemic lymphoma."
Ref: J Neurol Neurosurg Psychiatry 1998;65:191-195. Source: Community AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca
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Clinical application appears difficult. Regular screening for EBV via lumbar puncture is not feasible so pre-emptive therapy studies (with anti-CMV drugs?) would be impractical. Blood based markers would offer greater scope for investigation.
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HIV-positive patients and cardiac disease
Italian researchers estimate that 18.6% of AIDS patients have cardiac involvement at the time of death. They therefore believe that HIV-positive patients need to be closely evaluated for cardiac disease.
To determine the prevalence of cardiac involvement, Dr. Giuseppe Barbaro of the University "La Sapienza" in Rome and colleagues evaluated autopsy findings for 440 AIDS patients. Their report appears in the August 10th issue of AIDS Research and Human Retroviruses.
Overall, Dr. Barbaro's group detected cardiac involvement in 82 subjects. "Dilated cardiomyopathy was found in 12 patients; lymphocytic interstitial myocarditis was documented in 30 patients, and in 10 of 12 patients with dilated cardiomyopathy." Other findings included infective endocarditis (28 patients), pericardial effusion (53 patients), myocardial Kaposi's sarcoma (2 patients) and myocardial B-cell immunoblastic lymphoma (1 patient).
"Sequences of [HIV] nucleic acid were detected using the technique of in situ hybridisation in the myocytes of 29 autopsy patients," Dr. Barbaro's group reports. In addition, they identified active myocarditis in 25 of the 29 patients with a positive hybridisation signal.
They also noted that echocardiography detected cardiac involvement in 91.6% of the subjects in whom cardiac disease was subsequently confirmed by autopsy.
"HIV-associated cardiomyopathy may be related either to a direct action of HIV on the myocardial tissue or to an autoimmune process induced by HIV," Dr. Barbaro's concludes. "The increasing evidence of HIV-associated cardiac disease supported by autopsy and echocardiographic studies strongly suggests that a careful cardiological evaluation should be made to detect an early involvement of the heart in HIV-positive subjects."
Ref: AIDS Res Hum Retroviruses 1998;14:1071-1077.
Source: CDC Daily News Update
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Clinically relevant cardiac disease before PI's was extremely rare and these autopsy findings may not reflect symptomatic disease in the general HIV-infected population. Theoretically there may be a possible interaction of ischaemic heart disease due to raised lipids with PI use and subclinical cardiomyopathy. Some of these reported changes at autopsy may have been due to i.v. drug use rather than directly attributable to HIV (ie. infective endocarditis). |
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ON THE WEB
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- NNRTI's - A Class Whose Time Has Come.
This comprehensive online program summarises the latest data on non-nucleoside reverse transcriptase inhibitors (NNRTIs) presented in Geneva, reviewing recent studies that suggest that they may have comparable efficacy to standard PI-based combinations.
- Update on Wasting, Metabolism and Altered Body Shape in HIV.
A summary of presentations by world-renowned experts at the state-of-the-art Geneva Satellite Symposium, including the latest theories about lipodystrophy syndrome associated with HIV and protease inhibitors.
- Drug-Drug Interactions in the Clinical Management of HIV.
Newly updated with the latest data from the 12th World AIDS Conference. This program for HIV care providers by Charles Flexner, MD, and Stephen C. Piscitelli, Pharm.D., contains two unique components: An interactive program that allows you to select a multi-drug regimen and receive immediate feedback on potential interactions; and a one hour educational module on drug-drug and drug-food interactions.
The above programs are all available on the Clinical Care Options for HIV website at:
National AIDS Manual and BHIVA Website
Aidsmap, a new AIDS website owned by NAM and the British HIV Association (BHIVA) is available to give access to information on research and treatment through NAM's publications:
AIDS Treatment Project Website
AIDS Treatment Project runs its own website providing access to an archive of all back issues of the Doctor Fax, details of services and other treatment information produced by the group including information targeted at people with HIV. Also available online are the full-texts of the ATP booklets "A Guide to Combination Therapy" and "A guide to Second Line and Salvage Therapy" - both revised August '98. Web address:
All these publications are also available in print, as well as our new consumer-oriented HIV treatment magazine Positive Treatment News (PTN). Please call the AIDS Treatment Project office for free single or bulk copies.
AIDS Treatment Project St Stephens House 115-129 Southwark Bridge Road LondonSE1 0AX Tel: 0171 407 0777 Fax: 0171 403 4262 Email: admin@atp.org.uk Web site: www.atp.org.uk U.K. TREATMENT INFORMATION PHONELINE 0645 470 047 (Mon & Wed 6-9pm)