Important note: Information in this article was accurate in November 2002. The state of the art may have changed since the publication date.
While IDSA is generally not the venue for breaking HIV treatment data, there was some new information regarding laboratory monitoring strategies for resource-poor countries, rising HIV risk behaviors, adherence, complications of therapy, and vaccines presented at this year's conference in Chicago.
Developing surrogate measures predictive of immunocompromise that are inexpensive and feasible for use in resource-poor settings will be critical to the success of AIDS treatment in Africa. Spacek and colleagues presented an analysis comparing strategies for identifying patients who would benefit clinically from initiation of HAART in settings where flow cytometry is not consistently available [Abstract 27]. Within the Johns Hopkins HIV cohort database, a CD4 count of 200 cells/mm3 was correlated with a total lymphocyte count (TLC) of 1200, adding validity to the recent WHO recommendations for initiation of HAART [Scaling Up Antiretroviral Therapy in Resource-Limited Settings]. Adding a second criterion of hemoglobin <12 g/dL improved the predictive value of TLC alone for both men and women. When the TLC value was "intermediate," using hemoglobin increased the sensitivity of detecting a CD4 count <200 cells/mm3, suggesting that this might be a useful low-cost staging strategy in resource-poor settings where HAART will be initiated.
Syphilis and HIV: Syphilis may be mounting a resurgence among those with HIV infection, particularly among men who report same sex contact as an HIV transmission risk. Wong and colleagues reported estimates of syphilis incidence in San Francisco among HIV-infected men [Abstract 665]. Health department surveillance data indicated that syphilis incidence among men with HIV infection was approximately 525/100,000. A second estimate was calculated from additional serologic testing for syphilis performed on specimens sent for HIV viral load testing from 10 HIV primary care sites. The latter method indicated a primary/secondary syphilis rate of 1864 cases/100,000 (The current rate for the U.S. population as a whole is 2.2 cases/100,000). The authors concluded that syphilis rates among HIV-infected men were extraordinarily high in their community and that effective prevention programs targeting those with HIV infection, particularly men who have sex with men, are urgently needed.
Reducing STD risk in those with HIV infection: Preventing those with known HIV infection from continuing to expose others to HIV is a critical component of the U.S. HIV prevention strategy. Data on high risk sexual and drug use behaviors in women admitted to the inpatient HIV service at Jackson Memorial Hospital in Miami, Florida suggest that the hospital setting might provide opportunities to address transmission behaviors intensively [Brewer TH, et al. Abstract 543]. Among 73 hospitalized women, 80% had symptomatic AIDS, but only 27% were prescribed HAART. Twenty-nine percent reported >4 sex partners in the past year, with 14% reporting recent exchange of sex for money or drugs. Inconsistent attendance at primary care visits was also common, with fewer than 25% keeping 2 or more scheduled primary care visits over the past year. Overall, the findings demonstrate that hospitalized patients may benefit from aggressive case management to improve individual health outcomes, but also that the hospital setting may provide a unique opportunity to improve community health outcomes through more aggressive STD screening and risk reduction interventions.
HAART "Dry Run": Mock trials using candy have been advocated as a way to familiarize patients with the rigors of taking antiretroviral therapy and potentially to improve adherence when actual therapy is initiated (http://www.hivatis.org). However, like many commonly cited adherence interventions, this strategy is untested. Eggleston and co-workers randomized 60 patients initiating HAART to a 2-week mock trial of methylcellulose capsules (designed to approximate the planned antiretroviral regimen) or no intervention [Abstract 488]. In an intent-to-treat analysis, 65% of patients in the mock trial arm achieved HIV RNA <400 c/mL compared to 59% in the control group (P=NS), indicating no benefit from routine use of mock ART trials.
Adherence and Resistance: Non-adherence is widely believed to be the most important determinant of viral suppression and development of drug resistance. However, evidence increasingly suggests that the relationship between adherence and resistance is not linear. Howard and colleagues monitored antiretroviral adherence with MEMS caps in 114 HIV-infected patients on methadone maintenance in New York [Abstract 460]. Adherence was strongly associated with viral load suppression. A subset of 30 patients with virologic failure during the study (HIV RNA >1,000 c/mL) had genotype resistance assays performed. Among this viremic subgroup, the mean number of resistance mutations was 1.3 in patients with low adherence and 4.8 among those with high adherence (P=0.009). A recently published study of IDV concentrations in hair samples of HIV-infected patients taking this drug also suggested a parabolic relationship between adherence and development of antiretroviral resistance [Bernard L, et al. Ann Intern Med 2002 Oct 15;137(8):656-9]. In this study, patients with viral suppression had the highest mean IDV concentration, viremic patients who had developed PI resistance mutations had an intermediate mean IDV concentration, and viremic patients without detectable PI resistance had the lowest mean IDV concentration. The hypothesis is that, in the absence of viral suppression, higher levels of adherence exert greater selective pressure on HIV, and create circumstances most favorable to progressive development of resistance.
Directly observed therapy (DOT): Interest in DOT for HIV continues to grow, particularly now that novel once daily HAART regimens can be fashioned [Singh K, et al. Abstract 485]. Lucas and colleagues reported that HAART DOT in a methadone maintenance clinic was associated with a trend toward a greater likelihood of achieving HIV RNA <400 c/mL compared to a matched, but non-randomized, comparison group receiving standard care (76% vs 54%, P=0.08) [Abstract 489]. Dieckhaus monitored adherence with electronic bottle caps in HIV-infected prisoners taking self-administered therapy (SAT) and as part of a DOT program [Abstract 484]. Mean adherence was 89% for SAT and 75% for DOT (P=NS). The author suggested that currently existing DOT programs in prisons should not be assumed to improve adherence compared to SAT, particularly if understaffed or associated with stigmatization. Randomized controlled trials of HAART DOT are now needed.
Coronary Artery Disease (CAD): It is clear that ART is associated with insulin resistance, hyperlipidemia, and centripetal obesity, all factors strongly associated with CAD. Major questions at this time include: 1) Are HIV-infected individuals at higher risk for CAD than matched patients in the general population? 2) Does HIV infection itself impart increased CAD risk? 3) Are specific antiretroviral agents associated with increased CAD risk? 4) If so, do drugs increase risk independently of identifiable effects on glucose and lipid metabolism?
In a symposium (S78), Judith Currier reviewed available evidence on the risk of CAD in HIV-infected patients. To date, the data from large cohorts are mixed. A report from Kaiser Permanente, including 14,823 and 189,628 person-years of follow-up in HIV-positive and HIV-negative men, respectively, suggests that CAD rates are significantly higher in the former rather than the latter group, regardless of treatment status in the former [Klein D, et al. J Acquir Immune Defic Syndr 2002 Aug 15;30(5):471-7]. In contrast, CAD rates were similar in HIV-infected, untreated men and age-matched men in the general population in a French study with 36,907 person-years of follow-up [Mary-Krause, et al. 8th CROI, Abstract 657]. Both the Kaiser study above and a U.S. Veterans Health Administration study [Bozzette, et al. 9th CROI, Abstract LB9] found no evidence that PIs are associated with a higher risk of CAD. The latter study, involving 121,936 person-years of follow-up, reported slightly decreasing rates of admission for cardio- or cerebro-vascular events in HIV-infected patients from 1993 to 2001 (1.6 to 0.9 events/100 person-years), despite dramatic increases in the use of PIs and steep declines in overall mortality (18 to 5 deaths/100 person-years). In contrast, a small study from Frankfurt noted a significantly increased risk of CAD with HAART use [Rickerts V, et al. Eur J Med Res 2000 Aug 18;5(8):329-33]. Similarly, the French study found a dose-response relationship, with longer duration of PI use associated with increased rates of CAD events [Mary-Krause, et al. 8th CROI, Abstract 657]. Undoubtedly the picture will be clearer in upcoming years. HAART has only been in widespread use for 5 years, and substantial lag time would be expected between use of new therapies and CAD events, particularly in age groups at low baseline risk for CAD.
Gynecomastia and EFV: There have been case reports of gynecomastia in patients on efavirenz-containing regimens [Caso JA, et al. AIDS 2001 Jul 27;15(11):1447-8]. In a retrospective case control study, Rahim and colleagues found that EFV-containing regimens were strongly associated with the development of gynecomastia (OR 20, 95% CI 4.86-88.94) [Abstract 472]. No other anti-retroviral agent was associated with this finding. Prolactin levels were normal in seven cases in which it was measured. Prospective studies in which patients are randomized to regimens that do or do not contain EFV, such as ACTG 384, may help clarify the timing and strength of the association between gynecomastia and EFV-containing regimens.
HHV-8: M. Gandhi from UCSF presented a study on the rate of HHV-8 shedding in HIV infected women in the WIHS cohort [Abstract 826]. In a study of 66 women, the rate of HHV-8 shedding in saliva was higher in women whose CD4 count was >350 cells/mm3 and whose CD4 cell count nadir was never <200/mm3. One possible explanation for this finding is that CD4 cells promote HHV-8 replication in other cell types, such as B cells. Orogenital or oral-oral transmission of HHV-8 may account for the continued high prevalence of this infection in men who have sex with men during a time period that HIV-1 prevalence has fallen [Osmond DH, et al. JAMA 2002 Jan 9;287(2):221-5].
Two presentations focused on reviewing the current status of HIV vaccine development. Feinberg from Emory discussed recent studies of a number of vaccine candidates that result in control of viral replication in animals but do not induce sterilizing immunity [Symposium 17].
If such approaches work in humans, control of viral replication may delay progression to clinical disease and slow transmission. Feinberg pointed out that widespread smallpox vaccination, if adopted to counter bioterrorism threats, may interfere with one promising strategy for boosting HIV immune responses, the viral vector modified vaccinia Ankara, which is related to the smallpox vaccine. Graham from the NIH reviewed the HIV vaccine pipeline [Symposium 79]. Graham reported that canarypox vaccination will not go forward in U.S. phase III trials since the rate of CTL response induced was only about 15-20%. DNA vaccines and recombinant adenovirus vectors are going forward in human trials. Of note, these strategies are also being tested as therapeutic vaccines for individuals who already have HIV.
Addo from Bruce Walker's group presented data on CD8+ cytotoxic T lymphocyte (CTL) responses in 50 HIV-1 controllers (i.e. subjects with VL <1000 c/mL) [Abstract 30]. The CD8 immune responses in these individuals were most commonly directed against regions of HIV gag, pol and nef, but every HIV gene product can be targeted in infected individuals. Importantly, there was no difference in either the magnitude or breadth of the CD8 response between HIV-1 controllers and 29 untreated HIV+ individuals who were not controllers. There may be other immunologic explanations for viral control, such as the maturity of CD8 cells or the level of HIV-specific CD4 helper responses. This study suggests that in evaluating HIV vaccine strategies, we will need to assess the functional characteristics of the immune response in addition to the magnitude and breadth.
This year's IDSA included a smattering of new data across a broad range of HIV topics. In resource-poor areas, total lymphocyte count and hemoglobin may provide a cost-effective surrogate to CD4 cell count monitoring. Skyrocketing rates of syphilis in MSM in San Francisco make the case that risk reduction strategies are urgently needed. Use of DOT for ART continues to attract attention as once daily regimens become more available. HAART seems likely to increase CAD risk in some, but observational studies to date have produced mixed results. Finally, while vaccine progress is being made, new insights into the complex interplay between HIV and the immune system continues to underscore the challenges of this endeavor.
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