Comparative Immunovirological and Clinical Responses to Antiretroviral Therapy Between HIV-1 Group O and HIV-1 Group M Infected Patients.

BACKGROUND: Little is known about impact of genetic divergence of human immunodeficiency virus type 1 group O (HIV-1/O) relative to HIV-1 group M (HIV-1/M) on therapeutic outcomes. We aimed to determine if responses to standardized combination antiretroviral therapy (cART) were similar between groups despite strain divergence. METHODS: We performed an open nonrandomized study comparing the immunological, virological, and clinical responses to cART based on 2 nucleoside reverse transcriptase inhibitors plus 1 ritonavir-boosted protease inhibitor, in naive and paired HIV-1/O vs HIV-1/M infected (+) patients (ratio 1:2), matched on several criteria. The primary endpoint was the proportion of patients with undetectable plasma viral load (pVL, threshold 60 copies/mL) at week (W) 48. Secondary endpoints were the proportion of patients with undetectable pVL at W24 and W96 and CD4 evolution between baseline and W24, W48, and W96. RESULTS: Forty-seven HIV-1/O+ and 94 HIV-1/M+ patients were included. Mean pVL at baseline was significantly lower by 1 log for HIV-1/O+ vs HIV-1/M+ patients. At W48, no significant difference was observed between populations with undetectable pVL and differences at W24 and W96 were not significant. A difference in CD4 gain was observed in favor of HIV-1/M at W48 and W96, but this was not significant when adjusted on both matched criteria and pVL at baseline. CONCLUSIONS: Our data demonstrate similar immunovirological and clinical response between HIV-1/O+ and HIV-1/M+ patients. They also reveal significantly lower baseline replication for HIV-1/O variants, suggesting specific virological properties and physiopathology that now need to be addressed. CLINICAL TRIALS REGISTRATION: NCT00658346.

Resistance profiles after different periods of exposure to a first-line antiretroviral regimen in a Cameroonian cohort of HIV type-1-infected patients.

BACKGROUND: The lack of HIV type-1 (HIV-1) viral load (VL) monitoring in resource-limited settings might favour the accumulation of resistance mutations and thus hamper second-line treatment efficacy. We investigated the factors associated with resistance after the initiation of antiretroviral therapy (ART) in the absence of virological monitoring. METHODS: Cross-sectional VL sampling of HIV-1-infected patients receiving first-line ART (nevirapine or efavirenz plus stavudine or zidovudine plus lamivudine) was carried out; those with a detectable VL were genotyped. RESULTS: Of the 573 patients undergoing VL sampling, 84 were genotyped. The mean number of nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) mutations increased with the duration of ART exposure (P=0.02). Multivariable analysis showed that patients with a CD4+ T-cell count < or =50 cells/mm(3) at ART initiation (baseline) had a higher mean number of both NRTI and non-NRTI (NNRTI) mutations than those with a baseline CD4+ T-cell count >50 cells/mm(3) (2.10 versus 0.56; P<0.0001; and 1.65 versus 0.76; P=0.005, respectively). A baseline CD4+ T-cell count < or =50 cells/mm(3) predicted > or =1 NRTI mutation (adjusted odds ratio [AOR] 7.49, 95% confidence interval [CI] 2.20-32.14), > or =1 NNRTI mutation (AOR 4.25, 95% CI 1.36-15.48), > or =1 thymidine analogue mutation (AOR 8.45, 95% CI 2.16-40.16) and resistance to didanosine (AOR 6.36, 95% CI 1.49-32.29) and etravirine (AOR 4.72, 95% CI 1.53-15.70). CONCLUSIONS: Without VL monitoring, the risk of drug resistance increases with the duration of ART and is associated with lower CD4+ T-cell counts at ART initiation. These data might help define strategies to preserve second-line treatment options in resource-limited settings.

Tolerability and effectiveness of first-line regimens combining nevirapine and lamivudine plus zidovudine or stavudine in Cameroon.

We compared the tolerability and effectiveness of two major first-line regimens used in resource-limited settings, namely zidovudine-lamivudine-nevirapine and stavudine-lamivudine-nevirapine. HIV-1-infected adults in Cameroon were enrolled in a prospective cohort study between 2001 and 2003. They were eligible if they had AIDS or a CD4 cell count below 350/mm(3), a Karnofsky score over 50%, and no contraindications to antiretroviral treatment. The patients were followed up to 2 years. Of 169 patients, 85 received zidovudine-lamivudine-nevirapine and 84 stavudine-lamivudine-nevirapine. The incidence rates of treatment changes, death, drug resistance, and severe adverse effects were, respectively, 12.0 [95% confidence interval (CI) 7.2-19.9] and 10.9 (CI 6.4-18.3) per 100 person-years; 5.7 (CI 2.8-11.4) and 7.6 (CI 4.2-13.7); 2.9 (CI 1.1-7.7) and 5.0 (CI 2.4-10.6); and 41.7 (CI 30.2-57.6) and 49.1 (CI 36.1-66.6). The Kaplan-Meier curves for the likelihood of remaining on the initial regimen (p = 0.8) and for survival (p = 0.5) did not differ significantly between the groups. In Cox multivariate analysis only a lower baseline CD4 cell count was associated with death (p < 0.001). The proportion of patients with undetectable viral load and the increase in the CD4 cell count were similar in the two groups. Anemia was rare (4% vs. 6%). Five cases of severe peripheral neuropathy and one case of lipodystrophy occurred. This study suggests that the zidovudine-lamivudine-nevirapine combination is a safe first-line treatment, even in settings with few laboratory resources. In view of stavudine toxicity, these results support recommendations calling for a gradual switch from stavudine- to zidovudine-based regimens.

Field assessment of generic antiretroviral drugs: a prospective cohort study in Cameroon.

OBJECTIVE: To assess the effectiveness of generic anti-retroviral drugs in terms of survival and virological and immunological responses, as well as their tolerability and the emergence of viral resistance. METHODS: A total of 109 HIV-1-infected patients were enrolled in a prospective cohort study in Yaoundé, Cameroon. Available generic drugs were a fixed-dose combination (FDC) of zidovudine (ZDV) and lamivudine (3TC), an FDC of 3TC, stavudine (d4T) and nevirapine (NVP), and individual formulations of ZDV, 3TC and NVP. RESULTS: At baseline, the median CD4 cell count was 150/mm3 [interquartile range (IQR) 61-223] and median viral load was 5.4 log10 copies/ml (IQR 4.8-5.6); 78% of patients received ZDV/3TC/NVP and 22% received 3TC/d4T/NVP. Median follow-up was 16 months (IQR 11-23). The survival probability was high (0.92 at 12 months); plasma viral load declined by a median of 3.3 log10 copies/ml and 86.9% of the intention-to-treat population had viral load <400 copies/ml at 12 months; CD4 count had increased by a median of 106 cells/mm3 at 12 months; drug resistance rarely emerged (incidence rate 3.2 per 100 person-years); and the treatments were reasonably well-tolerated (incidence rate of severe adverse effects 7.8 per 100 person-years). CONCLUSION: Together with previous pharmacological and clinical studies, this prospective study suggests that these generic antiretroviral drugs can be used in developing countries.

Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial.

BACKGROUND: Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine. METHODS: 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis. FINDINGS: At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per microL (IQR 78-167) and median plasma HIV-1 RNA was 104?736 copies per mL (40804-243787). The proportion of patients with undetectable viral load (<400 copies per mL) after 24 weeks of treatment was 80% (95% CI 68-89). Median (IQR) change in viral load was -3.1 log10 copies per mL (-2.5 to -3.6) and in CD4 count 83 cells per microL (40-178). The probability of remaining alive or free of new AIDS-defining events was 0.85 (95% CI 0.73-0.92). Frequency of disease progression was 32.0 (95% CI 16.6-61.5), severe adverse effects 17.8 (7.4-42.7), and genotypic resistance mutations 7.1 (1.8-28.4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. INTERPRETATION: Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.

Biological and genetic characteristics of HIV infections in Cameroon reveals dual group M and O infections and a correlation between SI-inducing phenotype of the predominant CRF02_AG variant and disease stage.

In Yaounde, Cameroon, HIV-1 group-specific V3 serology on 1469 HIV-positive samples collected between 1996 and 2001 revealed that group O infections remained constant around 1% for 6 years. Only one group N sample was identified and 4.3% reacted with group M and O peptides. Although the sensitivity of the group-specific polymerase chain reaction (PCR) in two genomic regions was not optimal, we confirmed, in at least 6 of 49 (12.2%) dual O/M seropositive samples and in 1 of 9 group O samples, dual infection with group O and M viruses (n = 4) or with group O or M virus and an intergroup recombinant virus (n = 3). Partial env (V3-V5) sequences on a subset of 295 samples showed that at least eight subtypes and five circulating recombinant forms (CRFs) of HIV-1 group M co-circulate; more than 60% were CRF02_AG and 11% had discordant subtype/CRF designations between env and gag. Similarly as for subtype B, the proportion of syncytium-inducing strains increased when CD4 counts were low in CRF02_AG-infected patients. The V3-loop charge was significantly lower for non-syncytium-inducing strains than for syncytium-inducing strains but cannot be used as an individual marker to predict phenotype. The two predominant HIV-1 variants in Africa, CRF02_AG and subtype C, thus have different biological characteristics.

No difference in clinical progression between patients infected with the predominant human immunodeficiency virus type 1 circulating recombinant form (CRF) 02_AG strain and patients not infected with CRF02_AG, in Western and West-Central Africa: a four-year prospective multicenter study.

To compare human immunodeficiency virus (HIV) type 1 disease progression in patients infected by the predominant strain circulating recombinant form (CRF) 02_AG in western and west-central Africa and in patients infected by other strains, a prospective multicenter cohort study was conducted in Cameroon and Senegal. Among the 335 patients, a broad HIV-1 group M subtype diversity was observed in the envelope V3-V5 region, but strain CRF02_AG predominated in both Cameroon and Senegal (61.2% and 62.9%, respectively; P<.8). Multivariate analyses showed no difference between patients infected by CRF02 strains and those infected by other strains in terms of survival (adjusted hazards ratio [HR], 1.16; 95% confidence interval [CI], 0.76-1.78; P=.5), clinical disease progression (HR, 0.79; 95% CI, 0.50-1.25; P=.3), or square root CD4 cell decline (regression coefficient, -0.01; 95% CI, -0.82 to 0.81; P=.9). This study suggests that the predominance of HIV-1 CRF02_AG strain in western and west-central Africa should have no major clinical consequences.