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Report from the 12th Retrovirus Conference

This year's Retrovirus Conference returned to Boston, and despite predictably wintry weather, the premier scientific HIV meeting again attracted researchers and clinicians from all over the world. Indeed, the conference continued its string of "sold out" engagements: With registration limited to 3500, many who missed the deadline were sorely disappointed.

As always, the conference offered a wide range of both basic and clinical research, and we at ACC have chosen the oral and poster presentations that we believe have the greatest relevance to clinical care. Of particular interest this year were several studies revealing a suddenly full drug-development pipeline, numerous updates on antiretroviral rollout efforts in the developing world, further discussion of the role of nevirapine for prevention of perinatal transmission, several "switch" studies showing improvement in lipoatrophy, and a more complete description of the now infamous New York patient who presented with multidrug-resistant virus and rapid disease progression (see ACC March 2005, p. 21). All abstracts, along with webcasts of symposia sessions, are available at the meeting website: www.retroconference.org. -- Paul E. Sax, MD

Acute and Recent HIV Infection

Understanding acute and early HIV infection is critical to our understanding of such issues as HIV transmission, vaccine development, resistance to antiretroviral agents, and basic pathogenesis. Studies presented at the conference add to this knowledge base.

To identify missed opportunities for diagnosis of acute infection, Hightow and colleagues interviewed acutely infected patients about HIV testing and prediagnosis illness [565]. The majority of people with symptomatic acute infection reported that they had sought care for their symptoms, but only 3 of 19 had their acute infection diagnosed at initial evaluation. A surprising 60% had health insurance, but few had sought care with their regular doctors. Most were evaluated at urgent-care clinics or emergency departments, underscoring the importance in these settings of enhanced awareness of acute HIV infection and access to better diagnostic approaches.

The value of early treatment for acute HIV infection is still under investigation. Two trials were conducted based on the premise that diminishing activation during early infection might reduce the susceptibility of T cells to HIV infection and thus slow the pace of disease. In the first trial, Rizzardi reported long-term benefit in patients treated with potent combination antiretroviral therapy plus 8 weeks of cyclosporine A (CsA) during acute HIV infection [567]. Compared with patients who received combination therapy alone, those who also received CsA had significantly higher CD4-cell counts and percentages and greater improvement in CD4:CD8 ratios up to 120 weeks. They also had a greater likelihood of achieving viral loads <50 copies/mL. In the second trial, Bloch reported less favorable results from a comparison of combination therapy with and without hydroxyurea (HU) [569]. Although rates of virologic suppression were similar in both groups, the HU blunted CD4-count increases, resulted in a higher rate of serious adverse events, and had no lasting effects through structured treatment interruptions (STIs). Taken together, these results suggest that reducing immune activation during acute HIV infection is a worthwhile therapeutic goal, but the outcomes will depend on the way the goal is accomplished. Notably, CsA is being evaluated further among patients with acute and early infection in the ACTG 5216 trial, which is comparing AZT + 3TC + abacavir + lopinavir/ritonavir with and without CsA.

Finally, Ho gave a formal poster presentation about the recently reported case of a New Yorker who rapidly progressed to severe immunosuppression after acquiring a multidrug-resistant virus [973b]. Several details are worth considering: The man had repeatedly tested HIV-negative between September 2000 and May 2003. In November 2004, he developed symptoms consistent with acute HIV infection and tested HIV-positive in December 2004 with a CD4 count of 80 cells/mm³ and a viral load of 280,000 copies/mL by PCR. He reported having insertive and receptive anal intercourse with numerous male partners.

Resistance testing revealed reduced genotypic and phenotypic susceptibility to all currently available PIs, to nevirapine, and to NRTIs (see Table 1, below). The virus had a syncytium-inducing phenotype when grown on MT2 cells and was dual-tropic for CXCR4 and CCR5. The PhenoSense replication capacity was 136 -- remarkably high for a virus with such extensive resistance. Moreover, in phylogenetic analysis, the virus appeared to have a unique pol sequence that has not been described previously. Further studies of the patient's HLA type revealed no alleles associated with rapid HIV progression and a normal CCR5 receptor phenotype.

These data provide a better context through which clinicians can discuss this case. Whether this turns out to be an unfortunate confluence of two well-recognized clinical events -- rapid HIV disease progression and transmission of drug-resistant virus -- or the harbinger of widespread dissemination of a highly resistant and highly virulent HIV strain remains to be seen. The fact that clinicians and the public were alerted to this case was a good thing, but the same doesn't hold for the sometimes-inaccurate information that followed in the popular press. Presenting more complete (and accurate) data at this scientific meeting was useful, especially since the case presentation was followed by reviews of prospective cohort studies that defined the rates of both rapid HIV progression and transmission of drug-resistant virus. -- Charles B. Hicks, MD

Studies of Approved Antiretrovirals

The conference was long on tantalizing data about new agents and drug classes, but short on exciting news of established therapies.

John A. Bartlett updated his well-known 2001 cross-study comparison of triple-drug regimens and their success in terms of pill burden (ACC Nov 2001, p. 110 and AIDS 2001; 15:1369). The current meta-analysis (sponsored by the manufacturers of lopinavir, ritonavir, and tenofovir) included 69 randomized trials involving treatment-naive people with follow-up through week 48 [586]. Overall, virologic response rates appeared to be improving over time. Regimens including NNRTIs or ritonavir-boosted PIs were found to provide better virologic suppression than those containing unboosted PIs or those comprised of triple-NRTIs. Boosted PI combinations provided superior CD4-cell responses to all other regimens evaluated. Although lower pill counts had been significantly associated with virologic response in the earlier analysis, this did not hold up in the current one. The authors concluded that the primary driver of response is regimen potency, not pill count. Notably, this analysis was not weighted by study size, even though the studies had anywhere from 32 to 405 subjects per arm.

Lampe evaluated data from five cohorts in North America and Europe and found that virologic success rates in the first year of therapy have improved significantly since the advent of potent combination antiretroviral therapy -- with the rate of virologic failure falling from 40% in 1996 to 25% in 2002 [593]. As with Bartlett's meta-analysis, the patients most recently treated tended to have lower CD4-cell counts and were also more likely to be female, to have acquired HIV through heterosexual contact, and to have been started on an NNRTI. The risk of virologic failure was lower among MSM, older patients, those with lower baseline viral loads, and those without an AIDS diagnosis at baseline.

Fischl presented data from ACTG 5116, in which my colleagues and I evaluated simplified class-sparing regimens among patients successfully treated with a first potent combination [162]. All subjects initially had advanced disease (viral load >80,000 copies/mL or CD4 count <200 cells/mm³), and most had previously taken 3- or 4-drug combinations containing indinavir. Participants were randomized to receive efavirenz with either lopinavir/ritonavir (NRTI-sparing) or 2 NRTIs (PI-sparing). The primary endpoint -- time to either virologic failure or toxicity-related study drug discontinuation -- strongly favored the PI-sparing arm. During a median follow-up of 110 weeks, significantly more patients discontinued therapy in the NRTI-sparing arm than in the PI-sparing arm (20 vs. 6, P=0.002), a difference driven primarily by increased triglyceride levels. Switching to efavirenz + 2 NRTIs resulted in lower rates of regimen failure and greater maintenance of virologic suppression with less toxicity over the long term. -- Judith Feinberg, MD

Treatment Interruption and Other Novel Treatment Strategies

Despite the well-documented success of chronic antiretroviral therapy, we still need creative strategies for the long-term management of HIV infection. One approach that continues to garner interest, as discussed by Diane Havlir in a symposium, is the induction-maintenance strategy [181; see webcasts for Friday]. In the FORTE Trial, Loveday observed a lower risk of virologic failure with a 4-drug induction regimen followed by a 3-drug maintenance regimen than with a standard 3-drug regimen [575]. Documented resistance was lower in the 4-drug arm, which may explain the superior outcome. In a separate study of patients with NRTI resistance, Duvivier reported that a dual boosted-PI regimen without any RT inhibitors often was successful at suppressing HIV replication to below the level of detection [578].

Structured treatment interruption (STI) is a strategy that still doesn't have a niche, as demonstrated by several new studies. Pogány reported on 70 patients in the Netherlands who had initiated combination therapy at CD4 nadirs >350 cells/mm³ [584]. After successful treatment for at least 1 year, 45 patients chose to interrupt therapy, and 25 chose to continue. In the STI group, no serious adverse events were observed, and the median CD4-cell count was higher at 36 weeks of interruption than it had been at treatment initiation. In another study, Prazuck described 94 patients who underwent prolonged STIs (lasting up to 50 months) after successful combination therapy [585]. Prior to STIs, patients had undetectable viral loads and a mean CD4 count of 866 cells/mm³; 47 patients had CD4 nadirs <350 cells/mm³, and three had experienced acute antiretroviral syndrome. During follow-up, therapy was resumed at CD4 counts <350 cells/mm³. Two factors predicted a quicker return to therapy: a lower baseline CD4 nadir and a higher baseline viral load. In a similar group of patients participating in an ACTG study, my colleagues and I evaluated the benefit of IL-2 prior to prolonged STI (n=47); we too found that CD4 nadir and the level of viral rebound at the start of STI were predictive of time to a CD4 count <350 cells/mm³ [582]. Finally, in a small study in India (n=40), Kumarasamy observed initial positive outcomes among patients who received 6 months of generic combination therapy and then underwent STIs in a week-on/week-off cycle [583]. This approach cost half as much as continuous therapy, but it also raises concern about resistance; more studies are needed.

Salvage therapy is another setting where STIs have been utilized. Previous data from the CPCRA 064 study suggested that a 4-month STI was unhelpful in improving response to salvage therapy (see ACC Oct 2003, p. 86 and N Engl J Med 2003; 349:837). These results were confirmed by Lawrence in a final analysis: In the setting of low CD4-cell counts and broad virologic resistance, STI was associated with unfavorable CD4-cell response and a strong trend toward increased clinical progression that persisted even after combination therapy was restarted [579]. In the CTN 164 study, which involved a similar patient population (n=134), Walmsley found that a 12-week STI was of no benefit before a regimen switch in patients experiencing virologic failure [580]. No significant differences were observed between the STI and comparison groups in terms of the percentage of patients who achieved viral loads <50 copies/mL for 3 months, and the STI group had a significantly lower increase in CD4-cell count at 60 weeks. Finally, Beatty reported the results of a small study (n=30) comparing the immediate use of enfuvirtide/optimized background therapy versus a 16-week STI first [581]. The STI did not improve virologic response at 24 weeks. Taken collectively, these results confirm the wisdom of a recent editorial advising against STI in the setting of advanced HIV disease and treatment failure (N Engl J Med 2003; 349:827). -- Keith Henry, MD

Immune-Based Therapies for Established HIV Infection

Research continues on whether the immune system can somehow be manipulated to improve control of HIV replication and decrease immune damage with or without antiretroviral therapy. Therapeutic vaccination is an approach that has often been attempted but with disappointing results. Several investigators evaluated the efficacy of therapeutic vaccination by examining immune response. Wilson tested a multi-epitope DNA vaccine in patients doing well on antiretroviral therapy and found that vaccine recipients had no greater response to vaccine-related epitopes than placebo recipients [527]. In a very small pilot study with a similar population, Dorrell observed an increase in gag-specific immune responses (compared with controls) from a recombinant modified vaccinia virus Ankara gag/polyepitope vaccine [526].

Two studies examined therapeutic vaccination in the context of immune-modulating therapy. Kilby conducted an ACTG pilot study to evaluate whether therapeutic vaccination (canarypox HIV-specific immunogen [vCP1452]) with or without IL-2 could reduce virologic rebound during structured treatment interruption (STI) [525]. At 11 to 12 weeks after STI, viral load was significantly lower in the vaccine group than in the control group (median, 4.3 log copies/mL vs. 5.6 log copies/mL; P=0.01). IL-2 did not improve vaccine effectiveness. Although this study was small and had a fairly high dropout rate, it does suggest that an HIV vaccine could improve host immune control. In the QUEST Study, Samri evaluated whether antiretroviral therapy plus vCP1452 with or without Remune (inactivated virus particles) would prove effective in patients with primary HIV infection [524]. Based on a laboratory measure of immune response, there was no benefit to vaccination.

Several other immune-based therapeutic interventions are also under investigation. Tambussi reported an intriguing benefit for patients with primary infection who added mycophenolate mofetil to antiretroviral therapy before an STI [514]. Northfelt evaluated the effect of four weekly IV infusions of Cytolin (an anti-LFA mouse monoclonal antibody) in 11 patients who were either treatment-naïve or stable on fixed regimens [518]. At a dose of 2 mg/kg, Cytolin was associated with a 25% increase in CD4-cell count and a 1-log decrease in viral load. Rizzardi conducted a small feasibility study to assess the use of stem-cell gene therapy with non-myeloablative conditioning using cyclophosphamide (CY) [522]. The CY caused an initial marked decline in CD4-cell count, leading the authors to recommend the use of non-lymphocyte-toxic conditioning.

Finally, there is continued interest in the use of IL-2 in select patient populations. Lopez studied 118 subjects who had good viral control with poor immune reconstitution [516]. At baseline, patients had a median CD4 nadir of 24 cells/mm³ and a median CD4 count of 129 cells/mm³; 89% had undetectable viral loads. To date, 72 patients have completed three cycles of IL-2. Their median CD4 count has increased to 182 cells/mm³ (P=0.001); 37% have achieved a CD4-cell count >200 cells/mm³, and 88% still have an undetectable viral load. Although none of the patients have developed a new AIDS-defining event, all of them remain on OI prophylaxis. The clinical efficacy of IL-2 use should still be confirmed in a clinical-endpoint trial, such as the SILCAAT Study.

Taken collectively, these studies suggest that immune-based therapies are not yet ready for prime time, but that stepwise progress is being made to better understand and manipulate the HIV-damaged immune system. -- Keith Henry, MD

Adherence

Most adherence studies do not compare adherence levels and outcomes across different drug classes. Bangsberg, however, reported that in a well-characterized cohort of 110 homeless people, NNRTI therapy led to better virologic suppression than single, unboosted PI therapy [616]. Virologic suppression (<400 copies/mL) was common among NNRTI-treated patients in the three highest adherence quartiles (54% to 100% of doses) -- but was seen in the PI-treated patients only in the highest adherence quartile (>95%). After adjustment for adherence, the odds of virologic suppression were 5.6 times higher for NNRTI-treated patients than for PI-treated patients (P=0.001). Although virologic suppression appears to be achieved at lower adherence levels with NNRTIs than with PIs, the low genetic barrier for high-level resistance among NNRTIs may mean that near-complete adherence remains necessary to achieve durable virologic suppression for all regimens. Indeed, this was demonstrated in an earlier presentation by Bangsberg (XV International AIDS Conference, Bangkok, July 2004. Abstract WePeB5820).

Petersen evaluated the utility of serum bilirubin as a marker of adherence to atazanavir and found a significantly higher increase in bilirubin levels among virologic responders (1.0 mg/dL) than nonresponders (0.2 mg/dL) [745]. A bilirubin increase of at least 0.3 mg/dL was thought to be a potential marker for adherence, with a sensitivity of 81% and a specificity of 61%. Additional large-scale prospective studies are being performed to validate these retrospective findings. -- Gerald H. Friedland, MD, and G. Sonia Nagy, MD

Resistance

As noted in the acute infection section, Ho provided detailed information on the widely publicized case of a patient with multidrug-resistant HIV and rapid disease progression [973b]. Included was a complete description of the patient's resistance testing. Genotype results are summarized in Table 1; phenotype testing showed resistance to all antiretroviral agents except efavirenz and enfuvirtide, although the presence of some NNRTI mutations at baseline makes the supposition of efavirenz susceptibility somewhat tenuous. Further follow-up of this patient's treatment response to his efavirenz- and enfuvirtide-containing regimen will be important.

View this table: [in a new window]   Table 1. Genotype Results for a Case with Multidrug-Resistant HIV and Rapid Disease Progression.

 

In a poster from the same research group, Shet reported that 28 of 112 patients (26.7%) referred to this group for acute or recently acquired infection had evidence of at least some resistance [289]. Although this is not a surveillance study and may be biased given that the cohort was referred, it is alarming that NNRTI resistance increased from 2.6% during 1995-1998 to 13.4% during 2003-2004. Of even greater concern is that 11 patients (11.2%) had resistance to all three major antiretroviral classes. A more broadly representative sample was described by Bennett as part of the CDC's surveillance study of newly diagnosed (but not necessarily newly infected) individuals in 6 states [674]. For the period 2003-2004, some degree of genotypic resistance was found in 14.5% of 787 patients. In contrast with an earlier report from this group (see ACC September 2004, p. 76, and J Infect Dis 2004; 189:2174), resistance has now become most common to the NNRTI class, occurring in 8.4% of patients. This finding is particularly worrisome given the widespread use of NNRTIs as part of initial therapy.

Although NNRTI resistance is well documented in women who receive single-dose nevirapine for prevention of perinatal transmission, such resistance has less frequently been observed in patients who receive a suppressive NNRTI-based regimen and then stop all of their medications at once. However, in an analysis of the Tibet study, which is evaluating a CD4-driven treatment-interruption strategy, Ruiz reported that 8 of 19 patients on an NNRTI-containing regimen developed NNRTI resistance during the first or second treatment interruption [679]. These findings call into question the safety of CD4-driven treatment interruption in patients with virologic suppression on an NNRTI-based regimen, and indicate that such patients should either (a) switch to a boosted PI prior to stopping treatment or (b) discontinue the NNRTI several days to a week before stopping the NRTI component. Although theoretically plausible, neither strategy has been tested rigorously and proven to prevent resistance.

Little is known about management of patients with the K65R mutation because this mutation was rarely seen before the widespread use of tenofovir as part of initial therapy. In a series of patients who had experienced virologic failure on a triple-NRTI regimen of 3TC + tenofovir + abacavir (n=14) or 3TC + tenofovir + efavirenz (n=8), Landman reported that 19 were able to achieve viral loads <50 copies/mL at a median of 48 weeks of follow-up on salvage therapy [710]. Although somewhat limited by the fact that these subjects had a wide range of antiretroviral options to which their virus would be susceptible (notably boosted PIs), these data provide some reassurance that salvage therapy is likely to be successful when K65R develops on an initial regimen. -- Paul E. Sax, MD

New Drugs

Industry-sponsored posters and oral presentations highlighted "coming attractions" in HIV drug development. Several agents and classes look particularly promising.

PIs: Among drugs in development from existing classes, perhaps the most enticing data were presented by Haubrich on the investigational PI TMC114, which is being developed by Tibotec [164LB]. In this phase II/III study, 497 triple-class treatment-experienced patients with at least one primary PI mutation were randomized to receive an optimized background regimen plus 1 of 4 doses of ritonavir-boosted TMC114 or a comparator PI-based regimen. Although all TMC114/ritonavir doses were superior to comparator regimens at 24 weeks, the 600 mg/100 mg twice-daily dose performed best, with a mean viral load reduction of 1.85 log copies/mL and 47% of patients achieving viral loads <50 copies/mL. Particularly impressive was a subset analysis that showed 31% of TMC114-treated patients reaching viral loads <50 copies/mL, even when no active drugs were in the background regimen, versus 0% in the placebo arm. Adverse reactions occurred at similar rates in all treatment arms.

The next PI likely to be approved is tipranavir, which was shown in the RESIST studies to be more active than comparator PIs in patients with extensive PI resistance (see ACC Jan 2005, p. 5). In a new subset analysis of the RESIST data, Cooper reported that tipranavir was more active than lopinavir/ritonavir for patients who were either on lopinavir/ritonavir or resistant to it at baseline [560]. No significant difference in response was observed for patients who were lopinavir/ritonavir-naive or who had lopinavir-sensitive virus. An interesting finding from this analysis was that both the tipranavir and comparator PI arms did better when enfuvirtide was used in the background regimen. This beneficial effect was strongest in patients naive to enfuvirtide, but it was present even in those with prior exposure.

Another investigational PI currently in phase I/II studies is Glaxo Smith Kline's 640385, which shows excellent activity against PI-resistant viruses in vitro. Ford reported that in a pharmacokinetic study of healthy volunteers, 640385 was well tolerated over a short dosing period (15 days) [563]; based on levels targeted to have activity against resistant viruses, it will be dosed twice daily with low-dose ritonavir-boosting in studies with HIV-infected subjects.

NNRTIs: Drug development in the NNRTI class has been disappointingly slow, with several investigational compounds tested and discarded since the approval of efavirenz in 1998. Capravirine may well be added to this list of failed compounds: A study summarized by Pesano showed that the addition of capravirine to a nelfinavir-based regimen for NNRTI-experienced patients did not significantly improve virologic response [555]. In a much earlier phase of development is TMC278, a so-called "DAPY" (diarylpyrimidine) compound with a half-life of 38 hours; it was tested by Goebel in a phase IIa study of 47 HIV-infected treatment-naive men [160]. After 7 days of TMC278, patients treated with active drug experienced a viral load reduction of 1.2 log copies/mL versus no change for those treated with placebo. At the end of the treatment period, a standard antiretroviral regimen was started. Importantly, no new NNRTI mutations emerged during the treatment phase. Given that TMC278 has in vitro activity against some NNRTI-resistant viruses, further development of this compound is eagerly awaited.

Novel drug classes: For the first time, the promising integrase inhibitors showed an antiretroviral effect in humans: Little presented results from a 10-day dose-finding study of L-870810, which demonstrated an HIV RNA reduction of 1.7 log copies/mL in treated patients [161]. Although this particular agent is no longer being developed due to preclinical animal toxicity, a related compound is going forward in phase II/III studies.

Also under investigation is PA-457, presented by developers as a "maturation inhibitor" that hampers the last step of virion processing and thus causes the production of defective, noninfectious virions. Although similar to PIs in this regard, PA-457 does not inhibit HIV protease. Martin reported that among HIV-infected subjects, various single doses of PA-457 reduced viral load by as much as 0.7 log copies/mL, and 8 of 12 patients at the two highest doses demonstrated viral-load reductions of at least 0.3 log copies/mL [159]. Based on an extremely long half-life [551], once-daily dosing of PA-457 will be explored in phase II studies.

Finally, although no new data were presented on the antiretroviral effects of the investigational CCR5 inhibitors that are now in phase III studies -- Glaxo Smith Kline's 873140, Pfizer's UK-427,857 (now maraviroc), and Schering D -- investigators addressed such diverse issues for these agents as receptor occupancy [77], drug interactions with other antiretroviral agents [663, 664], and cross resistance [96]. -- Paul E. Sax, MD

Metabolic Complications

Strategies to reverse established lipoatrophy: Previous studies have demonstrated improvement in lipoatrophy when d4T (and to a lesser extent AZT) is replaced with abacavir (see, for example, AIDS 2005; 19:1523). In addition, results from one prospective study suggest that lipoatrophy may be less likely to develop in patients who receive tenofovir rather than d4T as initial therapy (JAMA 2004; 292:191). Moyle reported the results of an open-label industry-sponsored study in which 105 patients with virologic suppression on combination therapy and moderate to severe lipoatrophy were randomized to substitute AZT (n=34) or d4T (n=71) with either abacavir or tenofovir [44LB]. Objective assessments of limb fat were obtained using DEXA scans. After 48 weeks, limb fat had increased significantly from baseline in both the abacavir- and tenofovir-treated groups. The two treatment groups did not differ significantly in regard to increases in limb fat or in bone mineral density, but receipt of tenofovir was associated with fewer discontinuations of study drug and more favorable changes in lipid profiles. The results suggest that both of these nonthymidine agents are effective in improving established lipoatrophy, albeit slowly.

If NRTIs contribute to the development of lipoatrophy, then regimens that don't include these drugs might be expected to improve lipoatrophy. Tebas reported the results of an ACTG study of antiretroviral-treated patients who were randomized to receive efavirenz + lopinavir/ritonavir or efavirenz + 2 NRTIs [40]. After 48 weeks, the median change in limb fat was +562 g in the NRTI-sparing arm and -246 g in the NRTI-containing arm, but the difference was not statistically significant. However, after a mean 104 weeks of follow-up, the difference between the treatment arms (+782 g vs. -900 g) was statistically significant. Unfortunately, patients randomized to the NRTI-sparing regimen experienced significantly greater increases in triglyceride and total cholesterol levels and were more likely to experience regimen failure. No differences in bone density were noted between treatment arms.

Murphy presented preliminary results from a similar ACTG study in which patients with peripheral lipoatrophy and virologic suppression on a regimen that included either AZT or d4T were randomized either to switch the thymidine analogue for abacavir or to switch their entire regimen to lopinavir/ritonavir + nevirapine [45LB]. Subcutaneous thigh fat and subcutaneous adipose tissue, as measured by CT scan, improved significantly by week 24 in both groups. Follow-up is ongoing to determine whether differences exist between these two approaches. Collectively, these two studies provide the first evidence in randomized trials to support the concept of using NRTI-sparing regimens to improve lipoatrophy. -- Judith Currier, MD, MSc

Cardiovascular disease: Data continue to accumulate on the cardiovascular risks associated with HIV and its treatment. Previous reports from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study suggest that the risk for myocardial infarction (MI) increases 26% for every year that patients are on potent combination antiretroviral therapy (see ACC Jan 2004, p. 2, and N Engl J Med 2003; 349:1993). El-Sadr presented an updated analysis from this study that included 76,577 person-years: 277 of the 23,441 study participants experienced a first MI (79 fatal), yielding an overall rate of 3.6 MIs per 1000 person-years [42]. Standard risk factors (e.g., smoking, male gender) contributed to MI risk; after adjustment for these, the risk for MI increased 17% for every year that patients took combination therapy. When the most recent lipid levels were added to the model, the per-year increase in risk associated with therapy was reduced to 10%. This finding suggests that some but not all of the relation between combination therapy and MI risk is explained by dyslipidemia. Of note, these authors found no association between CD4-cell nadir and future risk of MI. In a separate report from the DAD Study, Sabin noted that the cohort's cardiovascular risk profile has worsened over time, but the MI risk seems to have stabilized or decreased [866]. The reasons for this are not clear but could be due to successful risk-factor interventions or changes in HIV regimens.

In addition to MI risk, combination therapy has been linked to an increased risk for hypertension. Seaberg found a 0.6-mm Hg increase in systolic blood pressure for each year that men in the MACS were taking combination therapy [872], and Crane summarized data suggesting that hypertension risk is associated with specific medications rather than stage of HIV disease [873]. Despite the challenges of establishing causality, these results merit further evaluation. Reports also continue to describe an increased rate of pulmonary hypertension in patients on combination therapy [874].

Data linking combination therapy and increased cardiovascular risk are limited by short follow-up, a low number of events, and the common presence of other risk factors. Several new studies focused on whether predictors of cardiovascular risk in the general population might also be predictors of risk in the HIV patient population. For example, in an analysis of HIV-positive men on treatment, Falutz found that having a large waist circumference and elevated triglyceride levels predicted the presence of other cardiovascular risk factors, such as lipid/glucose abnormalities, higher BMI, and metabolic syndrome [865]. In another study, Hsue found elevated C-reactive protein (CRP) levels in HIV-positive individuals, but the levels did not correlate with other cardiovascular risk factors [864]. Whether the CRP elevations reflect chronic low-grade inflammation or actual cardiovascular risk remains unclear. Finally, three studies involving HIV-positive patients from Boston, Spain, and Italy demonstrated increased thickening of the carotid intima and/or rapid progression of atherosclerosis [861, 862, 863]. These findings are worrisome and support the need for more aggressive research on cardiovascular disease in HIV-positive patients. -- Keith Henry, MD

Hepatitis

This year's conference didn't include any groundbreaking developments in hepatitis C virus (HCV) coinfection -- unlike last year, when investigators presented three large randomized studies on pegylated interferon. Nevertheless, some new and important information became available.

Sulkowski presented sobering data on 61 HIV/HCV-coinfected patients who each underwent two liver biopsies a median of 2.8 years apart [121]. Seventeen patients (28%) were found to have unexpectedly progressed by at least two stages on the Ishak fibrosis score; these patients were more likely to have high HIV viral loads and persistent AST elevations. These results indicate that the recommended biopsy schedule for HCV-monoinfected patients (every 3 to 5 years) might not be sufficient for some HIV-coinfected patients.

Given the cost, inconvenience, and risks associated with routine biopsy, noninvasive staging strategies are being evaluated more closely. Sterling presented data from the APRICOT trial showing that a simple index using age, AST and ALT levels, and platelet number could accurately predict hepatic fibrosis [120]. Index scores 1.45 predicted an absence of fibrosis, whereas scores 3.25 predicted the presence of fibrosis. About 70% of the validation cohort had scores outside these cutoffs and would have been spared a liver biopsy. However, only 87% of these patients would have been staged correctly according to biopsy results. Although this model requires confirmation, the concept of using easily available parameters instead of liver biopsy is intriguing, especially if HIV-coinfected patients are shown to require shorter staging intervals. The 13% misclassification rate is not trivial, but we should keep in mind that the gold standard (liver biopsy) is also not perfect, given its propensity for sampling errors.

McGovern reported that hepatic steatosis was associated with HCV genotype 3 and the use of dideoxynucleoside analogues [950]. This may be important to consider when starting antiretroviral therapy in coinfected patients, given that hepatic steatosis is associated with progression of fibrosis. Mehta found that hyperglycemia and insulin resistance were also predictive of hepatic steatosis and fibrosis [952]. In both the APRICOT trial and a large EuroSIDA evaluation, PI- and NNRTI-containing regimens were of similar safety and efficacy in coinfected patients, refuting the claims of some PI manufacturers that PIs are inherently superior in this setting [951, 946].

Several researchers presented evidence that we're getting a better handle on treating hepatitis B virus (HBV). First, Jain found that HBV serotype A (the most prevalent) responded much better to all treatment modalities than other serotypes [934]. Adherence >90% and a lack of previous HIV therapy were also associated with treatment response. Interestingly, patients who received tenofovir + 3TC not only experienced the greatest decline in HBV DNA, but all eight patients who converted to HBeAb positivity had received this combination. Second, Peters presented ACTG A5127, the first head-to-head trial of adefovir versus tenofovir for treatment of hepatitis B in HIV-coinfected patients [124]. The intent-to-treat analysis confirmed the noninferiority of tenofovir, and the as-treated analysis demonstrated significant advantages and superior antiviral efficacy for tenofovir. Finally, Pessoa presented findings demonstrating the effectiveness of entecavir against HBV in coinfected patients, most of whom had 3TC-resistant HBV [123]. Entecavir was well tolerated, and no patient experienced sustained rebound.

Data also were presented on hepatitis vaccines. Gandhi found that isolated hepatitis-B core-antibody positivity was not indicative of protective immunity or past infection [937]. In this study, HCV-coinfected patients were less likely to respond to HBV vaccination than HCV-monoinfected patients. Cooper showed that such disappointing response rates can potentially be improved with the use of immunostimulatory adjuvants [510]. Nurutdinova provided evidence that confirmed a lower response rate to hepatitis A vaccine among HIV-positive versus HIV-negative individuals and showed that this phenomenon is more closely associated with a lack of virologic control than immunologic control [511]. -- Helmut Albrecht, MD

HIV/AIDS in Resource-Limited Settings

The estimated number of people receiving antiretroviral therapy in the developing world increased sharply in the second half of 2004 (from 400,000 individuals to 700,000), largely because of initiatives such as the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and the WHO's 3 x 5 strategy. However, Jim Kim from the WHO reminded us during the keynote lecture that even with this improvement, only 12% of the nearly 6 million people who need antiretroviral therapy are receiving it (see webcast for Opening Plenary).

One of the challenges in making therapy more widely available is identifying who is HIV-positive. Wanyenze presented data on routine HIV testing among hospitalized patients in Uganda, [18]. Among 120,000 yearly admissions, 67% of patients did not know their serostatus. The researchers enrolled 500 patients at admission and randomized them to either testing while in the hospital (intervention) or testing at a separate site at discharge (control). Seroprevalence in both groups was high (65% among intervention patients vs. 50% among controls). All of the intervention patients received their HIV test results, but only 62% of controls were tested at the site to which they were referred. The authors concluded that routine in-patient HIV testing was acceptable and allowed more patients to know their serostatus.

Gray reported that HIV incidence in Rakai, Uganda is higher in pregnant women (2.3/100 person-years) than in nonpregnant, nonlactating women (1.1/100 person-years), a finding that was not explained by sexual risk behavior [19]. Evidence is mounting to suggest that a significant proportion of HIV transmission is occurring as a result of contact with individuals who have acute HIV infection. However, viral-load testing to diagnose acute infection is difficult to implement in developing countries. Fiscus presented data on the use of two rapid tests (Unigold and Determine) along with p24-antigen assay to diagnose acute HIV [20]. With this combination, the researchers were able to detect as many as 80% of acute HIV infections presenting to an STD clinic in Malawi.

Kityo Mutuluuza presented a virologic subanalysis of data from the DART (Development of Anti-Retroviral Therapy in Africa) study -- a randomized trial of clinical and laboratory monitoring versus clinical monitoring alone among 3300 symptomatic antiretroviral-naive patients starting triple-NRTI therapy with CD4 counts <250 cells/mm³ [22]. Overall, 2466 (74%) of the patients have been started on AZT + 3TC + tenofovir, 300 of whom were included in this intent-to-treat analysis. Virologic suppression to <400 copies/mL and <50 copies/mL was achieved by 76% and 57% of participants, respectively. Among 47 patients with virologic failure, 12 never achieved viral suppression. Although the authors concluded that these data represent a good 24-week virologic response, many in the audience felt that the response was less than optimal, given that clinical trials of potent combinations now routinely see >75% of patients achieving virologic suppression to <50 copies/mL at 24 weeks. However, the presenter stressed that triple-NRTI therapy should not be abandoned in Africa, where TB/HIV-coinfection is common, making PI therapy impossible and NNRTI therapy risky. Indeed, 27% of the patients enrolled in DART have a prior diagnosis of TB.

Is the response to antiretroviral therapy different in patients in developing countries? Dabis compared the therapeutic response among approximately 3000 patients in developing countries and 12,000 patients in developed countries [23]. On average, patients in developing countries started therapy at lower CD4-cell counts than patients in the developed world (250 cells/mm³ vs. 107 cells/mm³). After adjustment for this, mortality was higher in developing countries than in developed ones. However, the proportion reaching undetectable viremia was similar at 6 months (approximately 70% in both groups). This suggests that immunologic and virologic responses to therapy are similar in developed and developing countries, but that efforts are needed to identify HIV-infected patients in the developing world at an earlier stage of infection (at least before the CD4 count is <200 cells/mm³).

Wawer explored the reasons for the gratifying and often-cited declining HIV prevalence in Uganda [27LB]. This decline has been ascribed to increased rates of safer-sex behaviors promoted by the ABC program, especially A (abstinence) and B (be faithful), and, to a lesser degree, C (condom use). Wawer extended the acronym by considering the contributions of HIV-related death (D), viral epidemiology/early infection (E), and potential future (F) effects of antiretroviral therapy.

Between 1994/1995 and 2002/2003, age-standardized HIV prevalence in Uganda declined significantly in all adults (18% to 11%; P=0.007) but not in adolescents aged 15 to 19. Incidence did not decline overall (1.3/100 person-years vs. 1.7/100 person-years). Condom use with casual partners increased significantly, particularly at younger ages. However, age of sexual debut declined in both sexes, and the proportions of young adults reporting sexual activity, nonmarital relationships, and multiple partners increased. Approximately half of all HIV transmissions occurred from index partners who had themselves recently seroconverted.

Approximately 70 more HIV-infected people died per year than were added through new infections, accounting for much of the observed decline in prevalence. HIV incidence, and thus the number of HIV transmissions, contributed by people in early-stage HIV infection remained relatively stable in this period. Therefore, antiretroviral therapy is unlikely to reduce HIV incidence because most transmissions occur prior to the index partner's eligibility for therapy. The upshot is that most of the declines in HIV prevalence in Uganda appear to be attributable to condom use and death, not abstinence and monogamy. Wawer warned that as the provision of antiretroviral therapy is scaled up, behavioral interventions should also be scaled up to prevent paradoxical increases in transmission and prevalence.

Malinowska-Sempruch addressed the HIV epidemic among injection drug users (IDUs) in Russia and the former Soviet Republics [50]. Although IDUs comprise approximately 82% of HIV cases in Russia, they comprise only 30% of HIV-infected patients currently receiving antiretroviral therapy, suggesting that this population is being denied treatment. The author concluded that if an explosive epidemic is to be avoided, harm-reduction interventions (such as needle exchange and methadone treatment for IDUs) are needed urgently. -- Carlos del Rio, MD, and Gerald H. Friedland, MD

Tuberculosis

The small amount of information presented on tuberculosis was hardly proportionate to its role in the epidemic, especially considering that TB is the leading cause of death in HIV-infected people. However, several presentations provided interesting information on therapeutic issues in coinfected individuals and the conference concluded with a superb talk by Burman on the treatment of TB and HIV disease [182; see webcasts for Friday].

The optimal duration of TB treatment in HIV-coinfected individuals remains unclear. Swaminathan presented data from a study in AFB-sputum-positive HIV/TB-coinfected patients who were randomized to receive 6 or 9 months of anti-TB therapy [141]. All patients received a standard TB regimen consisting of 2 months of isoniazid + rifampin + ethambutol + pyrizinamide, followed by either 4 or 7 months of isoniazid + rifampin. All drugs were given three times weekly at appropriate doses, and treatment was directly observed at each dosage for the first 2 months and once weekly thereafter. The mean baseline CD4 count was 201 cells/mm³, and none of the patients received antiretroviral therapy. The researchers randomized 158 patients, 122 of whom were evaluated at the end of TB treatment. Sputum smears were negative in 93% and 98% of patients in the 6- and 9-month arms, respectively. Cultures were negative in 99% and 95% of patients, respectively. The 16 relapses among study patients were equally distributed between the two arms. The researchers concluded that 6-month and 9-month regimens resulted in similar outcomes -- a finding of substantial importance in resource-limited settings with severely stretched TB programs.

Concomitant treatment of TB and HIV has been complicated by rifampin-induced reduction in drug levels of PIs and, to lesser degree, NNRTIs. Consequently, PIs are not recommended for use with rifampin-containing TB regimens, and the proper dose of NNRTIs remains controversial. These interactions are highly important in developing countries, where TB is endemic and rifampin is a critical component of therapy.

Child reported results from an industry-sponsored study on the effect of rifampin on the pharmacologic disposition of atazanavir [657]. Disappointingly, as has been the case with other PIs, rifampin significantly decreased the overall exposure of atazanavir by approximately 75% compared with controls receiving atazanavir alone. The C_MIN decrease was even greater (~95%). Such low drug levels are not adequate for a predictable virologic response. Studies are being planned to determine if adequate atazanavir C_MIN can be achieved with twice-daily dosing of atazanavir/ritonavir, but there are presently no well-documented and safe PI-containing regimens that can be administered with rifampin-containing TB therapy. (Rifabutin, which can be administered with boosted PIs, is not available in most developing countries.)

Given the pharmacokinetic interaction between PIs and rifampin, potent concomitant treatment of TB and HIV requires the use of NRTIs and either efavirenz or nevirapine. More information exists on the benefit and safety of efavirenz, but the proper dose of this agent when used with rifampin has not been resolved. My colleagues and I reported data on 20 patients who were treated concomitantly with a rifampin-containing TB regimen and a once-daily HIV regimen of ddI + 3TC + efavirenz [891]. Trough efavirenz levels were measured at several points both during and after rifampin therapy. All patients received a 600-mg dose of efavirenz. Clinical, virologic, and CD4-cell responses were excellent during concomitant administration and were maintained after completion of TB therapy. Efavirenz levels were somewhat consistent within subjects, but there was substantial intersubject variability. Drug levels did not predict clinical outcome or toxicity and were not associated with patients' weight or gender. We concluded that the 600-mg dose of efavirenz appears to be adequate in patients receiving rifampin. -- Gerald H. Friedland, MD

Opportunistic Infections

Few studies were presented in the area of classic OIs, especially considering that these diseases are enshrined in the name of the conference. Lucas presented data indicating that invasive pneumococcal disease occurs in approximately 4 per 1,000 HIV-infected individuals annually [139]. He concluded that widespread use of potent combination therapy has not led to declines in invasive pneumococcal infections. Similarly, my colleagues and I found no decrease in PCP-related hospitalizations in the U.S. since the advent of potent therapy in 1997 [881]. Solomon reported a retrospective study of recurrent meningeal symptoms as part of an immune reconstitution syndrome seen in 12 (24%) of 52 AIDS patients treated for cryptococcal meningitis over the course of 10 years [880]. Clearly, expanded use of antiretroviral therapy in developing countries will result in an increase in the presentation of immune reconstitution syndromes, a constellation of OI-associated disorders for which we still don't have clear management guidelines. -- Carlos del Rio, MD

HIV-Associated Dementia

Recent data indicate that the prevalence of HIV dementia may be higher in developing countries than in developed ones. Sacktor examined the effect of potent combination antiretroviral therapy on neurocognitive function in 20 HIV-infected individuals in Uganda [9]. Significant improvements in neurocognitive performance were demonstrated after 6 months of antiretroviral therapy. The authors concluded that the diagnosis of HIV-associated dementia should be an indication for initiating antiretroviral therapy in Sub-Saharan Africa. However, as noted in a lecture by Ellis, the current IDSA/DHHS guidelines for use of antiretroviral therapy in the U.S. provide no specific recommendations on the management of HIV-associated neurocognitive impairment [17]. -- Carlos del Rio, MD

Diagnostics

Several investigators described new methods for the rapid and reliable diagnosis of incident HIV infection. Suligoi reported that the avidity index for HIV antibody was 92.8% sensitive and 98.0% specific for recent infection among newly diagnosed individuals in Italy [968]. With this method, HIV-antibody-positive serum samples are divided into two aliquots -- one diluted with guanidine and the other with phosphate-buffered saline (PBS) -- and tested again using the ELISA assay. The avidity index is calculated as the ratio of the sample values for the guanidine and PBS aliquots. Values <1 are thought to represent recent infection (<6 months prior), based on the hypothesis that early antibodies are less likely to link with ELISA antigens in the presence of guanidine. The authors suggest that this is an inexpensive, reproducible, and effective method of recognizing recent HIV infections.

Viani evaluated the performance of the Determine HIV-1/2 rapid antibody test in pregnant women presenting to a Tijuana hospital for prenatal care or labor [789]. The test had high sensitivity (100%), specificity (>99.7%), and negative predictive value (100%). The positive predictive value was 80% for women in labor and 71% for women receiving prenatal care. The mean time between blood collection and test results was 80 minutes for rapid testing, compared with 33 hours for routine ELISA testing. This type of rapid testing, when used for patients presenting in labor without prior prenatal care, affords the last opportunity to intervene and potentially prevent perinatal HIV transmission.

Foster conducted a pilot project in Philadelphia that offered rapid HIV testing to minority children and young adults in community settings [761]. Of 248 tests performed, 4 represented new positives, for a seroprevalence of 1.6%. Of the individuals with positive results, all were black and non-Hispanic, 75% were heterosexual, 25% MSM, and 50% male. This type of community-based rapid testing could be useful in the identification of new infections, beyond those identified through pediatric and adolescent HIV programs. -- G. Sonia Nagy, MD

Perinatal Transmission

Controversy continues over the use of single-dose nevirapine (sdNVP) for the prevention of perinatal transmission in resource-poor settings. In a plenary session, McIntyre highlighted the issues, including concerns with the rapid and significant emergence of resistance following the use of sdNVP (particularly in women with subtype-C infection), implications of NVP resistance on later treatment with combination antiretroviral therapy, and concerns about NVP-associated toxicity in women with CD4 counts >250 cells/mm³ [8; see webcasts for Wednesday].

Previous data indicate that NVP levels are detectable 21 days after women take a single dose of the drug (ACC Sep 2004, p. 70) and that, in areas with a high prevalence of subtype-C virus, this tail of monotherapy could lead to resistance in up to 75% of mothers [8]. This estimate is based on conventional genotyping, but real-time PCR data presented by Loubser suggest that the rate of resistance might be substantially higher: Among women who received sdNVP in South Africa, conventional sequencing detected the K103N mutation in 50% of samples at 6 weeks, while real-time PCR detected it in 89% of samples [102]. Detection of the K103N mutation declined over time in most women, and there was no archiving of these mutations 1 year after sdNVP.

According to previous results from the Treatment Options Preservation Study, adding 4 or 7 days of AZT/3TC to cover the pharmacokinetic tail of NVP could reduce the rate of NVP resistance to about 10% (ACC Sep 2004, p. 70). Dabis presented data suggesting that the postpartum addition of short-course AZT/3TC might decrease resistance even more than expected [72LB]. In the DITRAME PLUS study, 329 women received AZT/3TC and sdNVP, followed by 3 days of AZT/3TC postpartum to cover the NVP tail. The overall frequency of resistance mutations at 4 weeks was 1.1% for NVP and 8.3% for 3TC; none of these women had resistance at baseline.

Two study groups evaluated potential alternatives to sdNVP. In the first study, presented by Shapiro, women and infants received AZT, and both were initially randomized to either sdNVP or placebo [74LB]. However, the protocol changed during the study, so that all infants received sdNVP and only the mothers were randomized to placebo. Four-week transmission rates were not significantly different between groups in either the original protocol (5.3% for mother-child sdNVP vs. 6.2% for mother-child placebo) or the revised protocol (4.3% for maternal sdNVP vs. 3.7% for maternal placebo). Toxicity rates were low and did not differ by treatment group with either protocol. The authors suggest that maternal intrapartum sdNVP might not be needed to prevent transmission. In the second study, presented by Palombi, 778 women received generic combination therapy for at least 14 days (mean, 74 days) [67]. Transmission rates for 515 deliveries were 4% at 1 month postpartum and 6% at 6 months' postpartum. The resistance rate 2 to 6 months after treatment cessation was 11.9%, with all resistance occurring in patients with subtype C infection. Grade 3 or 4 hepatotoxicity occurred in 6% of women, Stevens-Johnson syndrome in 1%, and rash in 2%. There were five deaths, although cause of death was not mentioned in the presentation. The authors concluded that combination therapy could safely reduce transmission rates with a low toxicity profile and less resistance than what has been reported with sdNVP use.

Thomas provided data on adverse events associated with NVP use in Kenya [809]. Among 155 breastfeeding women who received AZT/3TC + NVP from 34 weeks' gestation through at least 6 months' postpartum, 13 serious adverse events occurred resulting in the cessation of NVP. No correlation was seen between adverse events and CD4-cell counts, and almost all adverse events resolved with treatment cessation. Although these data are somewhat reassuring, the cohort was too small to detect rare catastrophic events.

Beyond the nevirapine debate, two investigators presented data on maternal health issues in HIV-infected women. Gonzalez-Tome found that the prevalence of gestational diabetes might be higher in HIV-infected women (7%) than in the general population (2% to 5%) [68]. Kuhn found no difference in mortality between HIV-infected women who abruptly stopped breastfeeding at 4 months and those who continued for at least 6 months [70].

Although prevention of perinatal transmission with combination antiretroviral therapy in developed countries has been extraordinarily successful, much remains unknown about how to adapt this progress to areas where it is needed most. Aggressive work is necessary to (a) minimize transmission, toxicity, and resistance; (b) maximize adherence and availability in resource-poor settings; and (c) preserve treatment options for women who might need them. In addition, prevention strategies should address the risks and benefits of breastfeeding to both mother and child and include effective treatment options for mothers who wish to extend breastfeeding. -- G. Sonia Nagy, MD

Vaccines, Microbicides, and Novel Prophylactic Interventions

Presentations on HIV vaccines revealed a new approach in this field: Instead of developing new vaccine candidates, many researchers are now focusing on identifying ways to improve the application of existing candidates (e.g., through new formulations, vectors, dosing schedules, and adjuvants) and on trying to define protective immunity.

One of the most anticipated presentations was Lévy's report of long-term data from the ANRS 093 trial, a French therapeutic-vaccine study in which patients received combination therapy either alone or with two vaccines and IL-2 [133LB]. Preliminary results from this study demonstrated enhanced cellular HIV-specific responses that resulted in improved control of viremia following structured treatment interruption (STI). Long-term data confirmed these early results, with time off therapy being significantly longer in the vaccine group than in the control group (177 vs. 89 days). Although interesting as a proof-of-principle study, the trial left more questions than it answered. Was the vaccine or the concurrently administered IL-2 responsible for the observed benefit? Would this work in less selected patients? Is the time off therapy (on-average, 4 months) worth the added side effects? Can we prolong this relatively short-lived benefit? The most important question in my mind, however, is whether these results can be duplicated outside the STI setting. More data are accumulating that STIs in chronic infection may not be beneficial or safe. This study added to these concerns, with six patients experiencing AIDS-defining events despite very close supervision. The real question is whether antiretroviral therapy plus vaccine is better than antiretroviral therapy alone. Notably, other therapeutic vaccination trials continued to show negative results (see also STIs, above).

Most vaccines prove problematic when tested in monkeys. So far, prime/boost regimens have universally failed to prevent systemic infection upon mucosal challenge with a virulent strain. Butera reported, however, that a multigene DNA/MVA vaccine prime/boost strategy was able to protect against systemic infection, even after repeated low-dose intrarectal SHIV challenge [134]. Subbarao, using a similar model, presented data from the first animal study of tenofovir as preexposure prophylaxis [136LB]. Researchers gave 12 macaques daily tenofovir, weekly tenofovir, or no tenofovir followed by multiple rectal challenges with SHIV. Although tenofovir was initially protective, all animals eventually became infected with repeated exposures. This may be a bad omen for the human study that is currently being conducted on preexposure prophylaxis with tenofovir.

Researchers also described some novel and fascinating strategies using microbicides.

Veazey presented data indicating that the intravaginal topical application of a small-molecule CCR5 inhibitor to five macaques completely protected the animals against vaginal SHIV transmission [128].

Genetically engineered bacteria are routinely used to produce antibiotics, and several groups evaluated their potential to also produce antimicrobial substances that can act as microbicides. Chancey and Boden got lactobacilli to produce anti-ICAM-1 antibodies and fusion inhibitors [530, 529]. If applied vaginally as probiotics, these lactobacilli could produce microbicides that prevent local and systemic infection. Similar effects to prevent rectal infection could be achieved by modifying enteric bacteria, as Henry did with E. coli [531].

It is unclear how effective a microbicide would need to be to have a significant effect on controlling the epidemic. Using Monte Carlo simulations, Wilson found that among female sex workers in high-prevalence areas, the daily risk of acquiring HIV would decrease by 20% to 30% with the use of a microbicide that was only 30% to 50% effective [538]. -- Helmut Albrecht, MD, and Carlos del Rio, MD

Conclusion

Over the next year, we'll be looking for follow-up on much of the information presented at the conference. Areas of particular interest include: results of larger efficacy studies of promising, yet-to-be approved agents (especially the CCR5 inhibitors); more detailed descriptions of antiretroviral rollout in developing countries; the status of single-dose nevirapine for prevention of perinatal transmission; and a sense of whether lipodystrophy is less prevalent now that we have some understanding of which treatments are most strongly associated with this complication. Comparatively little progress was reported this year on the treatment of hepatitis C coinfection. Hopefully the coming year will yield more encouraging developments in this area. -- Paul E. Sax, MD

— ACC Editors

Published in AIDS Clinical Care March 21, 2005