The profusion of HIV conferences dilutes the quality of the data and keeps us from our day jobs. Next year’s XVI International AIDS Conference will be held in Toronto (which is only a little farther from Baltimore by plane than the Brazilian conference center was from Rio by bus!). In between, we’ll have ICAAC, IDSA, EACS, and CROI, not to mention smaller meetings devoted to lipodystrophy, resistance, and pharmacology, just to name a few. Still, it’s encouraging to look back over a year’s worth of data, as spread out as it is, and realize that steady progress is being made in the management of HIV infection.
While treatment interruptions will continue to occur and may be needed in many HIVinfected patients over decades of treatment, data continue to amass from large well-conducted clinical trials suggesting that using STI as a strategy to lower cost or reduce drug toxicity places patients at higher risk of disease progression. These data also imply that delaying the initiation of HAART in patients with earlystage disease may not be as safe as we once believed.
Jean R. Anderson, M.D. and Barbara Wilgus-Wegweiser, C.R.N.P.
The XVI international AIDS Conference focused on several issues of importance for women with HIV infection. Presentations on prevention continue to highlight the challenges of risk reduction strategies in a world where women are often without power, while simultaneously offering the hope that new technologies such as microbicides will give women an opportunity for HIV prevention not dependent on the behaviors of their partners.
In summary, there were a few important hepatitis studies presented at IAS, emphasizing the importance addressing the high risk behaviors of many drug users, the need for education on risks of HIV and HCV transmission in those most at risk, the effectiveness of therapy for acute HCV infection, the importance of looking for seronegative HCV infection in immunosuppressed patients or those at high risk, and the potential limits of liver transplantation in HCV/HIV co-infected patients.
Over the past decade, a substantial body of research has established the role of stavudine in the pathogenesis of glucose abnormalities, lipid alterations, and body composition changes, most notably lipoatrophy. There are few data reporting on the risk of these changes in patients in the
developing world, where the use of stavudine is widespread.
In summary, ETV can be safely coadministered with methadone, ranitidine or omeprazole. This is fortunate, since these drugs are commonly used in the treatment of patients with HIV disease.
DRV, co-administered with ritonavir (RTV), is indicated for use as part of combination antiretroviral treatment of HIV-1-infected adult patients who are highly treatment-experienced or have virus resistant to multiple protease inhibitors.
Significant progress has been made in the availability of antiretroviral drugs for resource-poor countries. Now that HIV treatment is available in many of these countries, it is important to understand population differences that could affect the safety and efficacy of these drugs. It is also crucial that clinicians understand the basic principles of drug metabolism, since a number of drugs available in these settings share metabolic pathways with PIs and NNRTIs.
The approach to HIV serologic testing in the future will focus on normalizing the HIV test and minimizing barriers to testing. As systems of care move this CDC guideline to full implementation, medical providers should remain committed to ensure that patients know when an HIV test is being ordered and understand that it is voluntary.
The following is a summary of changes contained in the May 4, 2006 edition of the “DHHS Guidelines for the Use of Antiviral Agents in HIV-infected Adults and Adolescents.”
Clinical pharmacology received substantial attention during the 13th CROI, and several studies presented at this conference increased our understanding of drug interactions, therapeutic drug monitoring, and the pharmacokinetics of antiretrovirals in pregnancy.
In this larger study of treatment interruption in children residing in a resource-limited setting, no increases in toxicity or disease progression were observed. Such studies are important for guiding policies on the time to start therapy in children. Given the high rates of disease progression in the first year of life for HIVinfected infants, a planned CD4-guided treatment interruption strategy for older children who start HAART from infancy may make early therapy feasible for infants living in resource-poor settings where early infant diagnosis is possible.
Kelly Gebo, M.D., M.P.H. and Lucy Wilson M.D., Sc.M.
Overall, the 13th CROI revealed that OIs still occur, although less frequently than before. In addition, while overall mortality has decreased, non-AIDS related mortality remains a significant issue, particularly among IDUs. AIDS-related and non-AIDS-related malignancies remain a significant comorbidity in HIV infected patients. Managing concomitant drug and tobacco abuse, along with vigilant cancer screening are important in helping our HIV-infected patients reduce cancer risk.
Megan Wind-Rotolo Ph.D. and Joel N. Blankson M.D., Ph.D.
What are the clinical consequences of CD4 cell infection in GALT? While it appears that the poor reconstitution of CD4 cells at this site is not associated with major GI symptoms in most patients on HAART, the relatively high frequency of pathology seen by Baker and colleagues is concerning [Baker J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 41]. Confirmatory studies in larger cohorts of patients are needed. If reconstitution of GALT CD4 cells is important, then the work of Dandekar and colleagues [Guadalupe M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 39] would suggest that there is a major advantage to early treatment with HAART
Observational studies like the ones discussed here are subject to considerable selection bias: for example, the better outcome associated with early initiation of therapy may have more to do with characteristics of patients who are treated aggressively than with baseline CD4 counts. Nevertheless, it should not be surprising that cohort studies originally suggesting no benefit to early therapy are now beginning to detect differences with longer follow-up.
Therapy for hepatitis B virus (HBV) was addressed by Richard Colono with results from a trial of entecavir, a drug with potent anti-HBV activity and no activity against HIV [Colonno R, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 832]. Consequently, entecavir is an option for co-infected patients where it is used: 1) to treat HBV without treating HIV, 2) as an alternative to tenofovir to combine with lamivudine/ emtricitabine (3TC/FTC), provided at least two additional antiretroviral agents are used as well, or 3) to treat 3TC/FTC-HBV treatment failures.
Etravirine and darunavir are promising new additions to the NNRTI and PI classes, respectively, that appear to maintain good activity in heavily experienced patients. In each case, specific mutations have been identified that are associated with a poorer response to these drugs. The imminent availability of these agents underlines the importance of avoiding PIs and NNRTIs in “holding regimen” situations, where viral suppression is not possible but therapy is needed to delay clinical disease progression.
HIV-infected women with advanced disease, particularly in resource poor settings, may be at greater risk for poor pregnancy outcomes including preterm delivery, fetal growth restriction and neonatal mortality. Jan Walter and collaborators sought to examine the likelihood of improved fetal outcomes among HIV infected women in Zambia treated with cotrimoxazole during pregnancy [Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 126].
There appears to be agreement on the increased risk of cardiovascular disease in our patients, but the relative contributions of antiretroviral therapy, specific antiretroviral agents, and HIV itself remain unclear. Clinicians are reminded that controlling traditional risk factors is still the best approach. At this meeting, we learned that interrupting therapy may be unwise, and that there is evidence supporting earlier initiation of therapy. Fat loss and fat accumulation, while often occurring together, are distinct phenomena with separate risk factors. We are also seeing that some promising therapies, such as metformin or testosterone for fat accumulation, are ineffective and may have unwanted side effects such as exacerbation of lipoatrophy. Even those with evidence of some benefit, such as “glitazones” for lipoatrophy, only yield a mild improvement. The task of the clinician remains complex: to select treatment regimens that will maximize the likelihood of a durable virologic response while minimizing the potential for side effects and longterm toxicity.
A new generation of entry inhibitors that could be injected once a week, or even less frequently, would be a major advance in HIV therapy. The recent approval by the FDA of an inhaled version of insulin, another small protein, raises the possibility of inhaled or perhaps even transdermal application of T-999 or T-1144. Although human studies have yet to begin with these two peptides, it appears we may be on the verge of developing drugs that not only improve the convenience of drug delivery, but may make concerns about adherence a thing of the past for some agents. This could be
CROI’s version of “Rocky Mountain High.”
The results of ACTG 5095 finally put a critical question to rest: Is the standard, 3-drug regimen enough, especially in patients with high baseline viral loads or low CD4 counts? Apparently it is, at least if you’re using a potent “anchor drug” like EFV. With the exception of a few more cases of abacavir hypersensitivity, the addition of a fourth agent (in this case, a third NRTI) didn’t seem to do much harm, but it clearly didn’t do any good, either. Together, these results and the disappointing results with NRTI-sparing regimens (see my EACS summary in this issue) suggest that we’ll still be using two NRTIs plus a third agent for some time to come.
The Hippocampe study (ANRS 121) compared NRTI-sparing vs. NRTI-containing regimens in treatment naïve patients with CD4 counts <350 cells/mm3 or viral loads >100,000 c/mL [Duvivier C, et al. Abstract PS1/3]. The protocol allowed use of any NRTI except d4T and ddC; NNRTIs allowed were nevirapine (NVP) and efavirenz (EFV); PIs were ritonavir-boosted indinavir (IDV/r) and lopinavir (LPV/r). The original aim of the study had been to compare metabolic and morphologic toxicity between the arms, but the study was terminated early after an analysis of 36-week data by the DSMB showed a significant difference favoring the NRTI-based regimens by both intent-to-treat and on-treatment analyses.
Joseph Cofrancesco, Jr., M.D., M.P.H. and Todd Brown, M.D.
New analyses of existing studies continue to show higher rates of limb fat loss with d4T, and to a lesser degree with AZT, compared to other NRTIs. In addition, data were presented that continue to demonstrate the benefit of switching from thymidine analogs to ABC or TDF as treatment for lipoatrophy. An interesting study suggested that pravastatin increased limb fat; this gain appeared to be greater than that accomplished with a switch from d4T to another NRTI.
Documentation of the nature and degree of the exposure and the HIV status of the source patient is critical. Rapid testing of previously untested source patients is valuable in determining the need for PEP.
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