Antiretroviral efficacy and virological profile of a zidovudine/lamivudine/tenofovir disoproxil fumarate combination therapy in antiretroviral-naive patients.

OBJECTIVE: To study the antiviral efficacy and the mutations selected by a triple therapy with zidovudine (AZT), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF). METHODS: Antiretroviral-naive patients received 300 mg AZT/150 mg 3TC twice a day plus 300 mg TDF once a day in an open pilot study. Follow-up was assessed at baseline therapy (MO) and at months 1, 3, 6, 9 and 12. Reverse transcriptase (RT) genotypic resistance analysis and in selected cases, a recombinant drug susceptibility and replication capacity assay were performed from plasma RNA at baseline and in case of virological failure (VF); that is, rebound of viral load >50 copies/microl on therapy. RESULTS: Twenty-four patients were included. At baseline, the median CD4+ T-cell count was 443 cells/microl and the median plasma viral load (VL) was 4.38 log10 copies/ml. RT resistance mutations were observed at MO in 4 patients. At M12, the proportion of patients with a VL <50 copies/ml reached 88% using an on-treatment analysis and 67% with an intent-to-treat analysis. The median increase in CD4+ T cells at M12 was 94 cells/microl. Four patients had a VF on therapy: two with wild-type viruses, one with selection of M184V and thymidine analogue mutations (TAMs) on a background of TAMs, and one with selection of K65R and M184V, with a replication capacity at 2.4%/o. CONCLUSION: The virological response in our study demonstrates the antiviral efficacy of the AZT/3TC/TDF combination therapy, which needs further evaluation. The moderate frequency of selection of K65R could be due to the presence of AZT in the regimen.

Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data.

Non-B HIV-1 viruses are predominant in developing countries where access to antiretroviral drugs (ARVs) is progressively being intensified. It is important to obtain more data on the susceptibility of these viruses to available ARVs. CRF01_AE, CRF02_AG, and subtype C strains of HIV-1 obtained from untreated patients from Vietnam, Cote d'Ivoire, and India were analyzed for their in vitro susceptibility to NRTIs, NNRTIs, PIs, and an entry inhibitor (T-20) using a recombinant viral assay (PHENOSCRIPT). The corresponding viruses, which had been previously sequenced in reverse transcriptase (RT), protease (prot), plus envelope (env) C2/V3 genes and had therefore been fully characterized, were further sequenced in env HR1 + HR2 regions. CRF01_AE isolates are sensitive to NRTIs and NNRTIs with the exception of one isolate that exhibits a decreased susceptibility to NNRTIs associated with a I135T substitution in RT. CRF02_AG and subtype C viruses are sensitive to NRTIs and NNRTIs but some CRF02_AG isolates tend to be resistant to abacavir, potentially related to associated substitutions of RT at positions 123 (D123N) plus 135 (I135V). Whereas all but one CRF01_AE isolates are fully susceptible to PIs, some CRF02_AG and, more frequently, some subtype C isolates are resistant to atazanavir. The role of substitutions in prot at positions of secondary resistance mutations 20, 36, 63, and 82 is raised with a potentially crucial role of the V82I substitution. Finally, all viruses tested, regardless of the CRF or subtype, are fully susceptible to T-20.

Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy.

BACKGROUND: The transmission of drug-resistant HIV-1 can impair the virological response to antiretroviral therapy. Minority-resistant variants have been detected in acute seroconverters. We investigated the clinical relevance of the detection of majority and minority-resistant variants in an observational study in antiretroviral therapy naive, recently infected patients. METHODS: We included patients infected between 1996 and 2005, with a plasma sample obtained less than 18 months after seroconversion and prior to antiretroviral therapy initiation. Majority-resistant variants were determined by direct population sequencing. Minority-resistant variants were searched by allele-specific PCR for the mutations K103N and M184V in reverse transcriptase and L90M in protease. The association between resistance and viroimmunological response to antiretroviral therapy was estimated by using a piecewise linear mixed model. RESULTS: Majority-resistant variants were detected in 23/172 (13.4%) patients. Patients with majority-resistant variants had a lower mean plasma viral load and higher mean CD4 cell count at baseline compared with those without resistance. The decrease in viral load between 1 and 6 months on antiretroviral therapy was significantly steeper in patients with sensitive viruses compared with those with majority-resistant variants (P = 0.029). Minority-resistant variants were detected in 21/73 (29%) patients with wild-type viruses at sequencing analysis. The presence of minority-resistant variants did not modify baseline viral load and CD4 cell count and did not affect the changes in viral load and CD4 cell count. CONCLUSION: The transmission of majority-resistant variants, but not minority-resistant variants, influenced the response to antiretroviral therapy in this prospective study. The detection of the transmission of minority-resistant variants warrants further clinical validation.

Reduced bone mineral density in HIV-infected patients: prevalence and associated factors.

BACKGROUND: There is a high prevalence of bone demineralization among HIV-infected patients but mechanisms of alteration of bone turnover are still unclear and it is thought to be multifactorial. METHODS: A cross-sectional survey of 492 HIV-infected patients within the Aquitaine cohort estimated the prevalence of osteoporosis/osteopenia and investigated associated factors. Bone mineral density of total body, lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable analyses of the association with HIV disease status, treatment and anthropometric parameters were stratified according to gender. RESULTS: Median age was 43 years (interquartile range, 38-50); 73% were male; 19.7% patients had reached AIDS, 93.1% were treated with HAART; and 28.5% had lipodystrophy. Based on World Health Organization criteria, osteopenia was diagnosed in 54.6% of men [95% confidence interval (CI), 49.4-59.7) and 51.1% of women (95% CI, 42.6-59.6) and osteoporosis in 33.7% of men (95% CI, 28.8-38.6) and 8.3% of women (95% CI, 3.6-13.9). Using a polytomous logistic regression, older age, homosexual transmission group, low body mass index and low HIV plasma viral load were associated with the diagnosis of bone abnormalities in men, whereas older age and low CD4 lymphocyte count nadir were independently associated with osteoporosis/osteopenia in women. The use of HAART was not related to osteoporosis after adjustment (P = 0.58). CONCLUSIONS: This cohort-based survey showed a high prevalence of osteopenia and osteoporosis of multifactorial origin. Mechanisms and consequences of these bone disorders need to be investigated.