Causes and Consequences of Incomplete HIV RNA Suppression in Clinical Trials

Abstract

The current goal of antiretroviral treatment is suppression of HIV RNA below 50 copies/mL. However, there is evidence for residual low-level plasma viraemia below 50 copies/mL for people with HIV RNA suppression on antiretroviral treatment. It is not clear whether more profound suppression of HIV RNA would lead to a lower risk of virological failure on antiretroviral treatment or emergent drug resistance. There is high variability in the currently used HIV RNA PCR assays for samples with HIV RNA levels close to the detection lower limit of 40–50 copies/mL. For patients who have HIV RNA levels just above 50 copies/mL (often called “single blips”), a repeat sample should be taken to investigate the possibility of technical error. In a systematic review of 48-week effi cacy from randomized clinical trials (N = 8,083), patients were signifi cantly more likely to show HIV RNA levels between 50–400 copies/mL while taking fi rst-line boosted PI-based HAART (7.3%) compared with fi rst-line NNRTI-based HAART (4.5%) (p < 0.01). However in a systematic review of emergent drug resistance at failure in the same trials, there was also a signifi cantly lower risk of emerging drug resistance after virological failure of boosted PI-based HAART (p < 0.01). Therefore, HIV RNA blips between 50–400 copies/mL may have different consequences for different classes of antiretrovirals. The most widely used method to analyse HIV RNA in clinical trials — time to loss of virological response (TLOVR) — uses two consecutive HIV RNA measurements to define both virological success and failure. However, other methods may improve precision and increase statistical power.     

Determinants of Sustained Virological Suppression in Indigent,HIV-Infected Patients: Is Single Protease Inhibitor-Based Antiretroviral Therapy Truly Highly Active?

Abstract

Background: Effective virological suppression with HAART is dependent on strict adherence to therapy. Compliance with therapy is influenced by clinical and psychosocial factors. Method: We performed a retrospective study investigating determinants of effective virological suppression, defined as <400 RNA at 11-13 months of HAART, in an urban indigent population. The study included 366 new patients presenting for care to the Thomas Street Clinic, Houston, Texas, between April and December 1998. Median age, CD4 count, and viral load (VL) of the study population were 37.5 years, 189 cells/mm³, and 53,000, respectively. Thirty-nine percent had AIDS, 20% had cocaine-positive drug screens, and 64% were antiretroviral naïve. Two hundred and sixty-seven patients were started on HAART. Thirty-four percent showed virological suppression. Results: In multivariate analysis, adherence to HAART, care by experienced primary provider, baseline VL <100,000 copies/mL, age >35 years, and no active substance use were associated with virological suppression. Rates of virological suppression with HAART are unacceptably low in this urban indigent population. Conclusion: Low rates of virological suppression are primarily due to lack of adherence rather than late utilization of care among ethnic minorities. Single protease-inhibitor-based antiretroviral therapy does not appear to be highly active in this patient population.     

ABCB1 Allele Polymorphism Is Associated with Virological Efficacy in Naïve HIV-Infected Patients on HAART Containing Nonboosted PIs But Not Boosted PIs

Abstract

Objective: To assess the effect of the multidrug resistance-1 single nucleotide polymorphism (ABCB1 SNP) C3435T in exon 26 on the virological responses to first-line protease inhibitor (PI)-containing HAART regimens. Method: A cohort of 182 HIV-infected patients with a PI-containing HAART regimen initiated from 1997 to 2004 was enrolled. Time to the first indetectable viral load (VL) was determined in patients with the CC, CT, or TT genotype. Results: There were 37%, 44%, and 19% of patients who had the CC, CT and TT genotypes, respectively. The median estimated times to VL indetectability in the CC, CT, and TT groups were respectively 5.9, 3.9, and 4.8 months (p = .06). In patients on a non-boosted PI regimen, ABCB1 genotype was associated with time to VL indetectability that was shorter in patients with the CT than CC genotype (CT vs. CC, hazard ratio [HR] = 0.62, p = .02; TT vs. CC, HR = 0.72, p = .21). This association was not found in patients with first-generation boosted PI-containing regimens and especially not with second-generation boosted PI-containing regimens. Conclusion: Our results show that the ABCB1 SNP in exon 26 is associated with virological efficacy in HIV-infected patients treated with non-boosted PI-containing regimens but not with those containing boosted PIs, particularly of the second generation.     

Comparison of Nevirapine- and Efavirenz-Containing Antiretroviral Regimens in Antiretroviral-Naïve Patients: A Cohort Study

Abstract

Objective: Efavirenz (EFV) was superior to nevirapine (NVP) in two recent cohort studies; but data from clinical trials suggest that three studies are needed to validate cohort results. We performed a cohort analysis comparing time to treatment failure and change in plasma HIV-1 RNA from baseline in antiretroviral therapy (ART)-naÏve individuals treated with NVP- or EFV-containing regimens. Method: A cohort analysis of three observational databases (N = >10,000 patients) found 1,078 ART-naÏve individuals treated with NVP-containing (n = 523) or EFV-containing (n = 555) regimens. Patients were evenly matched and received at least three antiretroviral agents. The primary endpoint was time to treatment failure defined as a rebound in plasma HIV-1 RNA > 400 copies/mL. Other endpoints were change in plasma HIV-1 RNA from baseline and percent with plasma HIV-1 RNA <400 copies/mL over time. Potential confounding variables were analyzed using the Cox proportional hazards model. Results: Compared to EFV, NVP patients had a shorter time to treatment failure (307 days vs. 589 days; p < .001), less decrease in plasma HIV-1 RNA (-0.51 log vs. -1.32 log; p < .001), and fewer patients with plasma HIV-1 RNA < 400 copies/mL (45% vs. 51%; p < .001). Significant factors for failure were baseline CD4 count (per 100 cell increase) or viral load (per log increase), treatment center, and year of entry (p < .05 for all comparisons). Race, gender, and background nucleoside use were insignificant factors. Multivariate analysis that included significant factors for failure demonstrated improved relative hazard with EFV compared to NVP (odds ratio = 0.50, p < .001). Conclusion: EFV-containing antiretroviral regimens were associated with superior clinical outcome, as measured by time to treatment failure. Results are commensurate with other large cohort studies comparing EFV and NVP.     

Lipodystrophy in 685 HIV-1–Treated Patients: Influence of Antiretroviral Treatment and Immunovirological Response

Abstract

Purpose: To describe the clinical features in HIV-1-infected patients treated with protease inhibitors (PIs) or not, and to determine factors related to occurrence of lipodystrophy (LD). Method: We performed a cross-sectional analysis of 685 treated HIV-1-infected patients that were routinely followed in 6 Paris hospital centers between January and May 1999. Demographic data, familial and personal vascular risk factors, history of antiretroviral treatment, HIV plasma viral load, CD4 cell count, and metabolic data were collected. Clinical examination was based on an assessment of changes in abdominal, dorso-cervical, and breast girth and wasting of the limbs, face, and skin as quoted by the clinician. Results: The mean age at inclusion in the study was 38 years; 29.5% were women. At study assessment, 77.5% of patients were PI-treated and 22.5% had never received a PI. LD was observed in 403 (58.8%) patients, of whom 340 were currently receiving a PI and 63 had never received a PI. More than half of the lipodystrophic patients had a mixed form (53.9%), while 25.3% were classified as exclusive lipoatrophic and 20.8% as exclusive hypertrophic. In multivariate analysis, older age, duration of antiretroviral treatment (ART), antiretroviral combinations including stavudine, antiretroviral combinations including a PI, AIDS status, and a low HIV RNA were independently associated with occurrence of LD. Conclusion: LD is frequently observed in PI-treated patients, but it is also observed in patients receiving an ART regimen without PIs. Our study suggests different underlying mechanisms, because immunovirological response to treatment as well as certain therapies were linked to the occurrence of LD. This hypothesis would be best clarified in a large prospective cohort of naive patients.     

Hydroxyurea plus Didanosine as Maintenance Therapy for HIV-Infected Patients on Long-Term Successful Highly Active Antiretroviral Therapy

Abstract

Background: Toxicity and quality of life issues have moved to delay the initiation of highly active antiretroviral therapy (HAART) and to explore novel treatment strategies for HIV infection. The switch to simpler regimens or treatment discontinuation has been attempted with limited success. The combination of hydroxyurea (HU) plus didanosine (ddI) is a simple regimen that might be able to restrain virus replication for long periods of time and could be an acceptable option as maintenance therapy in patients on prolonged successful HAART. Method: The combination of HU (500 mg bid) plus ddI (400 mg qd) was offered to participants with viral load (VL) <50 HIV RNA copies/mL and CD4 counts >350 cells/μL for more than 6 months under HAART. The prior HAART regimen was resumed if VL rose to >5,000 copies/mL and/or the CD4 count fell to <200 cells/μL after being on HU + ddI maintenance therapy. Results: A total of 187 participants replaced HAART with HU + ddI. In an intent-to-treat analysis at 48 weeks, 109 (58%) and 77 (41%) patients had VL below 5,000 and 500 HIV RNA copies/mL, respectively. The mean CD4 count dropped from 809 ± 283 to 573 ± 270 cells/μL, while 77% of patients remained above 350 cells/μL. The proportion of participants with hypercholesterolemia declined from 70% to 46% (p < .001), while those with hypertriglyceridemia fell from 36% to 21% (p < .05). Significant improvements in lipohypertrophy and lipoatrophy were observed in 52% and 64% of participants, respectively. Grade 3-4 toxicities appeared in 20 patients (11%), including 3 cases of pancreatitis and 1 of peripheral neuropathy. Prior history of VL >5 log, CD4 counts <200 cells/μL, and ddI experience were independently associated with lower response to HU + ddI maintenance therapy. Conclusion: The combination of HU + ddI may be a satisfactory maintenance therapy for more than half of patients on successful HAART who want to alleviate drug-related toxicities and/or pill burden. Patients with metabolic and/or body-shape abnormalities might particularly benefit from switching to this simple regimen.     

Randomized Salvage Therapy with Saquinavir-Ritonavir versus Saquinavir-Nelfinavir for Highly Protease Inhibitor-Experienced HIV-Infected Patients

Abstract

Purpose: To compare saquinavir + ritonavir and saquinavir + nelfinavir with nucleoside recycling in patients with multiple failures of highly active antiretroviral therapy (HAART). Method: This was a prospective, multicenter, randomized open trial. Inclusion criteria were the following: consent, age > 18, previous protease inhibitor (PI) exposure > 6 months, unchanged HAART > 3 months, and viral load > 3 log. The treatments compared were ritonavir 200 mg bid + saquinavir 600 mg bid (Rito-Saq), and nelfinavir 1,000 mg bid + saquinavir 600 mg bid (Nelf-Saq). Nucleoside analogues were recycled, and nonnucleoside inhibitors were not permitted. Trough levels of the three drugs were measured by high-performance liquid chromatography at the month 3 visit. After the study had been completed, genotyping analysis was done on the first serum at entry. Results: The study was interrupted due to the availability of new anti-HIV drugs. A random sample of 31 (16 Rito-Saq and 15 Nelf-Saq) patients was divided into two groups, which were comparable in terms of demographic data and previous history of HIV infection. Mean CD4 cell count and plasma viral load (pVL) were 316 ± 169 and 3.89 ± 0.87 for Rito-Saq and 448 ± 238 and 3.85 ± 0.32 for Nelf-Saq. Previous duration of PI exposure was 31 months for both groups. The mean number of protease gene mutations was 3.8 (range, 2-7) and 4.4 (range, 2-9), respectively. On intention-to-treat (ITT) analysis at month 6, pVL stabilization or decrease ≥ 0.5 log was observed in 18 patients (58%): 10 for Rito-Saq and 8 for Nelf-Saq. In a multivariate logistic regression analysis, virological success at month 3 was inversely correlated to baseline viral load (R = 0.14; 95% CI 0.03-2.9; p = .01); and at month 6, virological success was inversely associated to the number of mutations in the protease gene (R = 2.2; 95% CI 0.73-6.53; p = .06). Conclusion: Nelf-Saq and Rito-Saq combinations can be proposed in case of multiple HAART failures. The fact that the virological response was inversely correlated to baseline viral load makes the case for an early switch after a HAART failure.