Bioterrorism clearly took center stage at this year’s IDSA meeting. Only one slide session was devoted to HIV-related issues, and, as in previous years, head-turning new data on antiretroviral therapy were sparse. However, there were some interesting abstracts presented on the pathogenesis early of HIV infection in women, opportunistic infections (OIs), and response to vaccinations.

Antiretroviral Therapy

• Viral Evolution During Effective HAART: Two groups added to the growing data on viral evolution during "suppressive" ART. Lisa Frenkel presented results of phylogenetic analyses on 10 children with a median follow-up of 4 years, in whom HIV RNA levels were below the level of detection for some portion of the study [Abstract 20]. Three patterns were observed. First, some children had no forward evolution on therapy as measured by longitudinal phylogenetic analysis of sequences from HIV DNA in peripheral blood mononuclear cells (PBMCs). In fact, viral sequences regressed over time to resemble sequences observed during an earlier stage of infection. This pattern was associated with therapy that included 4 or more antiretroviral agents, infrequent blips in HIV RNA, and > 1 log₁₀ decline in HIV DNA while on therapy. In the second pattern, no new resistance mutations were noted during therapy, but prior mutations that conferred a selective advantage to the current regimen increased in frequency, while mutations associated with agents used in prior regimens decreased in frequency. Third, some children had viral evolution and developed new resistance mutations over time, despite viral suppression at most time points. Persaud and colleagues conducted similar analyses on 20 HIV-infected individuals with HIV RNA consistently <50 c/mL, and reported a static and archival pattern of drug resistance mutations [Abstract 778]. The conclusion from these studies is that a continuum of viral replication (and subsequently evolution) probably exists in patients with "good virologic response" to HAART. It is likely that achieving the optimal result, namely arrested viral evolution and regression to an archival wild-type pattern, is associated with minimal prior therapy and antiretroviral resistance, a highly potent regimen, and rigorous adherence.
  
  
• When to Begin Therapy: In the past year there has been considerable interest in the issue of the optimal time to begin HAART in HIV-infected patients. Several presentations at the 8th CROI suggested that a CD4 count <200 cells/mm³ at initiation of HAART was associated a higher risk of mortality and disease progression [see Sterling, HHR 2001;13(2):1]. However, starting HAART in CD4 strata above 200 cells/mm³ was not associated with discernable clinical benefit [Phillips AN,et al. JAMA 2001 Nov 28;286(20):2560-7]. Sterling and colleagues presented data at IDSA illustrating some of the downsides of starting HAART when the CD4 count is relatively high [Abstract 687]. With a median follow-up of 29 months, 253 patients in the Hopkins cohort who initiated HAART with CD4 count >350 cells/mm³ were compared to 386 patients who started at lower CD4 cell counts. As has been previously shown by this group, HIV disease progression was not different in patients who did or did not start HAART when the CD4 cell count was >350 cells/mm³. However, at most recent follow-up, only 49% of those starting HAART at higher CD4 cell counts had VL<400 c/mL, while 49% had adverse drug reactions requiring regimen changes, 51% were on a second HAART regimen, and 5% were on a third HAART regimen. Lipodystrophy was reported in 11% and genotypic resistance in 22%. This study identifies the dark side of starting HAART in early HIV disease: frequent virologic failure, drug toxicity, and progressive accumulation of resistance.
  
  
• First Line Therapy: Parenti and colleagues presented 48-week follow-up of the COL30336 trial in which antiretroviral naïve patients were treated with AZT/3TC (Combivir), abacavir (ABC) and efavirenz (EFV) [Abstract 697]. The median CD4 count and VL at enrollment were 285 cells/mm³ and 5.1 log₁₀ c/mL, respectively, and 68% had a baseline VL >100,000 c/mL. By intent-to-treat analysis (switches included), 93% achieved VL <50 c/mL at 48 weeks and the median CD4 count had increased to 438 cells/mm³. Three patients were switched to didanosine for possible abacavir hypersensitivity reactions. This potent regimen is appealing because the addition of abacavir probably does not carry the risk of broader resistance if virologic failure occurs, as might be the case in a triple-class regimen. Some clinicians prefer to start with Combivir and EFV, and add ABC only if viral suppression is not achieved. A definitive comparison of these strategies is underway in an AIDS Clinical Trials Group study.
  
  Lucas and colleagues found that EFV-based therapy outperformed PI-based therapy in a clinical cohort setting [Abstract 686]. Treatment outcomes were compared in minimally experienced patients who started therapy with NRTIs plus EFV (n=61), a single PI (excluding saquinavir, n=416), or ritonavir and saquinavir (RTV/SQV, n=68). Viral suppression (<400 c/mL) was achieved by 72% in the EFV group, 51% in the RTV/SQV group, and 49% in the single PI group (P<0.05 for both comparisons with EFV). Discontinuation of the regimen within 4 weeks was strongly associated with the use of RTV. In patients who achieved viral suppression, the time to viral rebound (>1000 c/mL) was similar in the three groups, suggesting no differences in durability once viral suppression was achieved.
  
  
• Switch Studies: Recently, numerous trials have been presented demonstrating the safety of switching from effective PI-containing therapy to a PI-sparing regimen. Pulvirenti and colleagues presented similar findings in the COL30305 study [Abstract 689]. This trial included patients on a first PI regimen who had maintained VL <400 c/mL for at least 3 months with at least 2 documented VL <50 c/mL. Patients were randomized 2:1 to switch their PI for ABC or continue the PI. Methodologically this trial was somewhat cumbersome, in that patients randomized to ABC continued to take their PI for 4 weeks after starting ABC. Fifty-eight patients were randomized to ABC and 29 to PI continuation. By intent-to-treat analysis, 78% of ABC patients and 76% of PI continuation patients maintained viral suppression <50 c/mL at 24 weeks. Perfect 7-day adherence was reported by 92% of ABC recipients and 68% of PI-continuation patients at 24-week follow-up. Total and low-density-lipoprotein cholesterol were significantly lower in the ABC arm than in the PI arm. However, 8/58 in the ABC arm discontinued due to adverse reactions compared to 0/29 in the PI arm.
  
  Lieu and colleagues presented their experience with RTV-boosted IDV therapy in 66 patients with at least 1-year follow-up (49 patients switched from t.i.d. IDV, and 17 were previously IDV naïve). RTV and IDV were dosed at 100 mg and 800 mg b.i.d., respectively [Abstract 682]. The main finding of this study was the poor tolerability of the RTV/IDV regimen. Only 55% (36/66) of individuals remained on the regimen at 1-year. RTV/IDV was stopped because of nephrolithiasis (n=12), nausea (n=6), virologic failure with resistance (n=5), and rapid progression of hyperlipidemia or lipodystrophy (n=4). Although RTV/IDV used in this combination has potential advantages (simplified dosing, no food restrictions, and improved serum IDV concentrations), the results from this and other studies cast doubt on the long-term tolerability of this regimen.

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Primary HIV Infection in Women: Implications of Viral Uniformity or Diversity

Over the past few years interest in sex-based differences in HIV transmission and early pathogenesis has been growing. Women appear to have significantly lower viral loads than men, particularly during the first 3-5 years after seroconversion, although overall rates of disease progression are similar [Sterling, et al. N Engl J Med 2001;344:720]. It has previously been observed that when studied early after primary HIV infection, a majority of women in Africa have multiple viral variants compared to men, who tend initially to have a homogeneous viral population. Sagar and colleagues studied a cohort of female commercial sex workers in Kenya who were followed monthly with HIV-1 antibody testing and other evaluations [Abstract 21]. A qualitative heteroduplex assay was used for determining the presence of viral diversity in blood samples available at HIV seroconversion. Of 102 women who seroconverted during the study, 61 showed a heterogeneous viral population and 41 had viral homogeneity.

The heterogeneous and homogeneous groups had similar demographic characteristics and sexual behaviors, including condom use. Additionally, the presence of genital ulcer disease and other sexually transmitted diseases was similar in the two groups. Interestingly, use of a hormonal contraceptive was the only risk factor identified for a heterogeneous viral population at the time of HIV infection (OR 4.2, 95% CI 1.8-10.1). Compared to women with a homogeneous initial infection, women who were infected with multiple viral variants had higher viral setpoints (median VL 100,000 vs. 46,000 c/mL) and lower CD4 cell counts (390 vs. 460 cells/mm³) measured 4-12 months after seroconversion. Sagar hypothesized that hormonal contraception may lead to changes in the epithelial barrier in vaginal tissues that increase the risk of infection with multiple viral variants, and that early heterogeneous infection may be better able to allude the immune system and produce to rapid disease progression than an initially homogeneous viral population.

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Opportunistic Infections

As the rate of clinical disease progression has plummeted in developed countries since the introduction of HAART in 1996, the incidence of opportunistic infections (OIs) may have reached their nadir. McNaghten and colleagues from the CDC’s Adult and Adolescent Spectrum of HIV Disease project reported a leveling of OI rates in 1999 [Abstract 751]. This cohort includes approximately 20,500 HIV-infected individuals in 11 U.S. cities. The annual trends in incidence decreased for 20 of 26 OIs between 1995 and 1998. However, trends leveled off for 24 of 26 OIs between 1998 and 1999. McNaghten hypothesized that this trend may represent the peak effect of HAART in their cohort. As data become available from 2000, it will be interesting to see whether significant increases in OI rates are observed. Rebounding hospitalization rates in HIV-infected individuals have been reported in other cohorts [Gebo KA, et al. J Acquir Immune Defic Syndr 2001 Jun 1;27(2):143-52].

• A Simple, Accurate Blood Test for PCP? M. Skelly from NYU presented intriguing data regarding a potential diagnostic assay for Pneumocystis carinii pneumonia (PCP) [Abstract 19]. At present, confirming this diagnosis is often tricky. Examination of induced sputum for organisms has a poor sensitivity, frequently necessitating bronchoscopy with bronchoalvelolar lavage (BAL) to definitively confirm or rule-out PCP. Skelly's group observed that Pneumocystis carinii is the only known organism that is unable to synthesize S-adenosylmethionine (AdoMet), a critical biochemical intermediate, meaning that this pathogen is dependent upon a continuous external supply of this substrate. His group previously reported that serum levels of AdoMet decline in correlation with organism burden in a mouse PCP model.
  
  In the presented study, serum AdoMet levels were determined by high performance liquid chromatography in 15 PCP patients (7 confirmed, 8 presumed) and a variety of control groups. The median AdoMet concentration was 106 nM (range, 86-128) in 12 healthy controls but was below the limit of detection (0.5nM) in 14/15 PCP patients at presentation. The other PCP patient, who did have confirmed infection, had a concentration of 8 nM. Importantly, other more relevant control groups were also studied, including individuals with asymptomatic HIV infection, bacterial pneumonia, tuberculosis, and cryptococcosis. AdoMet concentrations in these other groups were not significantly different from those in healthy controls, and there was no overlap with levels in PCP patients. Additionally, AdoMet concentrations rose to normal within 1 week of successful therapy for PCP. Skelly reported that a cutoff of 25 nM would have had 100% sensitivity and specificity for PCP in their cohort. This promising assay deserves further prospective study, specifically where all enrolled participants are evaluated by the current gold-standard, BAL.
  
  
• Treatment of HIV/Hepatitis C Virus (HCV) Co-infection. Sulkowski presented preliminary results for the Hepatitis Resource Network Clinical Trials Group of a randomized study of ribavirin plus daily vs. thrice weekly interferon (IFN) -2b in HIV/HCV co-infected patients [Abstract 433]. IFN was dosed at 3 MU in both the daily and thrice weekly groups. Inclusion criteria included CD4 >100 cells/mm³ and compensated liver disease. Exclusion criteria included active drug or alcohol use or serious psychiatric illness. The two groups were similar with respect to baseline characteristics. In the on-treatment analysis, 33% in the daily IFN group achieved undetectable plasma HCV RNA levels at 12 weeks, compared to 13% in the thrice weekly group (P=0.01). The authors concluded that the superiority of IFN suggests that pegylated IFN (which has a long half-life and is dosed weekly) will be beneficial in the treatment of co-infected patients. As a side note, approximately one third of patients in each group dropped out of the study prior to 12 weeks. The authors suggested that this drop-out rate was largely due to problems with side effects and adherence.
  
  While these results are promising, they also point to the difficulties of using IFN and ribavirin in the co-infected population. Fleming and colleagues presented data from their clinic at Boston University echoing these difficulties in clinical practice [Abstract 755]. Of 93 co-infected patients in their clinic who completed evaluation for HCV treatment, only 31 (33%) were offered HCV therapy. Of the 62 who were not suitable for therapy, 26% were non-adherent with clinic visits, 24% had active psychiatric disease, 22% were actively using drugs or alcohol, and 23% had decompensated liver disease or medical contraindications to therapy. Of the 31 offered therapy, only 9 have commenced therapy at this point (6 have refused and 16 are deferring therapy). Thus, only 10% of those evaluated for HCV co-infection were eligible and agreed to start treatment.
  
  
• Management of High Intracranial Pressures (ICP) with Cryptococcal Meningitis. Garcia-Gonzalez and colleagues presented results from 21 patients with cryptococcal meningitis and elevated ICP (>200 mmH₂O) accompanied by headache and impaired consciousness who were randomized to repeated lumbar punctures (LP) or dexamethasone (0.15mg/Kg/d tapered over 15 days) [Abstract 760]. All were treated with amphotericin B (1mg/Kg/d), and all had LP performed on days 3, 7, 14, 21, and 30, to assess improvement. Patients assigned to repeated LP had LP performed daily with cerebrospinal fluid (CSF) drained until the ICP was less than 200 mm H₂O or was reduced by half in those with ICP >400 mm H₂O. The two groups had similar demographic and clinical features at presentation (mean ICP 260 and 350 mm H₂O in the dexamethasone and LP groups, respectively). Clinical improvement was observed in 89% in the dexamethasone group and 83% of the LP group at day 30 (one patient in the former and two in the latter group died). ICP fell rapidly in both groups. CSF fungal cultures were negative in 50% of the LP group, but only 22% of the dexamethasone group at day 14. However, by day 30 the microbiologic cure rate was similar in the two groups. This study suggests that repeated LP and dexamethasone have a similar clinical efficacy in patients with increased ICP from cryptococcal meningitis, but that the latter may be associated with slower sterilization of CSF.

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Response to Vaccination in HIV-infected Individuals

Studies in the pre-HAART era focused on the association between CD4 count and serological response to vaccines in HIV-infected patients. However, there is considerable ambiguity about what factors predict serological response to vaccines in patients on HAART, and which patients would be most likely to benefit. Huprikar and collaborators presented data suggesting that suppression of the viral load is an important predictor of response to vaccination, regardless of the CD4 cell count [Abstract 380]. The study was a retrospective review of 41 HIV-infected patients who received the 3-dose hepatitis B vaccine series and had follow-up hepatitis B serology performed.

Huprikar noted that the low seroconversion rate overall may have been a byproduct of the retrospective design and the broad time interval (2-14 months) between vaccination and determination of serologic response. The group is planning a larger, prospective study to better explore these issues.

Wallace and colleagues presented data indicating that hepatitis A vaccine with VAQTA (Merck) effectively produced seroconversion in HIV-infected patients, but that this group may be more dependent on the recommended 6-month booster than HIV-negative individuals [Abstract 379]. Sixty HIV-infected and 90 HIV-negative individuals were given the 2-dose hepatitis A series and were evaluated for seroconversion.

Not surprisingly, Wallace reported that hepatitis A seroconversion rates in HIV-infected patients with CD4 counts below 300 cells/mm³ declined linearly at lower CD4 counts, but this data was not presented.

In summary new data presented at IDSA suggest that potent antiretroviral therapy, which suppresses viremia to below detectable limits using standard assays, is generally not associated with viral evolution in long-lasting reservoirs. Women who use hormone contraceptives and acquire HIV sexually may be at increased risk for early infection with multiple viral variants, which may have implications for clinical disease progression. Additional data was presented showing the downside of starting HAART in early stage HIV disease, namely frequent virologic failure, adverse effects, and antiretroviral resistance. An assay for a serum biochemical intermediate, on which Pneumocystis carinii is uniquely dependent, may hold promise as a non-invasive diagnostic test for PCP. Last, data presented at the conference indicate that viral suppression on HAART may be as important a predictor of serologic response to vaccination as the CD4 cell count.

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