Withdrawing inactive NRTIs in HIV-1 subjects with suppressed viraemia: a randomized trial.

BACKGROUND: Extensively pretreated subjects with virological failure (VF) may receive salvage regimens containing NRTIs with only residual or no activity. Once virological suppression is achieved, their contribution remains elusive. METHODS: This was a multicentre, randomized, prospective study. Subjects with at least one prior VF, HIV-1 RNA <50 copies/mL for ≥6 months and receiving a regimen with at least two active drugs (one of them a boosted PI) were randomized 1:1 to stop (experimental arm) or maintain (control arm) NRTIs. EudraCT: 2012-000198-21. RESULTS: Ninety subjects were randomized (experimental, n = 45; and control, n = 45). The mean age was 50 years, 80% were male, the mean CD4+ cell count was 542 cells/mm(3) and the median number of prior VFs was 3. Seventy-four subjects (82%) harboured the mutation M184V/I and the median number of thymidine-associated mutations was 3 (IQR: 0-4). In the experimental arm, thirty-two (71%) subjects removed one NRTI and 13 (29%) subjects removed two. Twenty-two of 45 (49%) discontinued tenofovir disoproxil fumarate. Forty-one of 45 (91.1%, experimental arm) and 44 of 45 (97.8%, control arm) had HIV-1 RNA <50 copies/mL at 48 weeks (difference: -6.7%; 95% CI: -17.4, 4.1). In a post-hoc analysis allowing NRTI reintroduction, efficacy rates were 95.6% and 97.8%, respectively (difference: -2.2%; 95% CI: -7.2, 2.7). Rates of discontinuation at 48 weeks were 2% in both arms. One subject developed a late VF with resistance selection. CONCLUSIONS: In patients receiving a successful multidrug salvage regimen with at least two active drugs (one a boosted PI), the withdrawal of inactive NRTIs was safe, rates of VF were low and drug resistance was uncommon at 48 weeks in this small study. This strategy could potentially prevent long-term toxicities, reduce the number of drugs and reduce costs if non-inferiority was met in a fully powered trial.

Reproductive desire in women with HIV infection in Spain, associated factors and motivations: a mixed-method study.

BACKGROUND: Antiretroviral therapy has created new expectations in the possibilities of procreation for persons living with HIV. Our objectives were to evaluate reproductive desire and to analyze the associated sociodemographic and clinical factors in HIV-infected women in the Spanish AIDS Research Network Cohort (CoRIS). METHODS: A mixed qualitative-quantitative approach was designed. Women of reproductive age (18-45) included in CoRIS were interviewed by phone, and data were collected between November 2010 and June 2012 using a specifically designed questionnaire. Reproductive desire was defined as having a desire to be pregnant at present or having unprotected sex with the purpose of having children or wanting to have children in the near future. RESULTS: Overall, 134 women were interviewed. Median age was 36 years (IQR 31-41), 55% were Spanish, and 35% were unemployed. 84% had been infected with HIV through unprotected sex, with a median time since diagnosis of 4.5 years (IQR 2.9-6.9). Reproductive desire was found in 49% of women and was associated with: 1) Age (women under 30 had higher reproductive desire than those aged 30-39; OR = 4.5, 95% CI 1.4-14.3); 2) having no children vs. already having children (OR = 3.2; 1.3-7.7 3); Being an immigrant (OR = 2.2; 1.0-5.0); and 4) Not receiving antiretroviral treatment (OR = 3.6; 1.1-12.1). The main reasons for wanting children were related to liking children and wanting to form a family. Reasons for not having children were HIV infection, older age and having children already. Half of the women had sought or received information about how to have a safe pregnancy, 87% had disclosed their serostatus to their family circle, and 39% reported having experienced discrimination due to HIV infection. CONCLUSIONS: The HIV-infected women interviewed in CoRIS have a high desire for children, and the factors associated with this desire are not fundamentally different from those of women in the general population. Maternity may even help them face a situation they still consider stigmatized and prefer not to disclose. Health-care protocols for handling HIV-positive women should incorporate specific interventions on sexual and reproductive health to help them fulfill their procreation desire and experience safe pregnancies.

Clinical, virological and biochemical evidence supporting the association of HIV-1 reverse transcriptase polymorphism R284K and thymidine analogue resistance mutations M41L, L210W and T215Y in patients failing tenofovir/emtricitabine therapy.

BACKGROUND: Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. RESULTS: The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. CONCLUSIONS: Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

HIV-1 genotypic drug resistance interpretation rules - 2009 Spanish guidelines.

Interpreting the results of drug resistance tests for HIV-1 is one of the most difficult tasks for both clinicians and virologists. There are many amino acid changes in viral proteins influencing the susceptibility to specific drugs, causing loss of activity or conversely hypersusceptibility. Moreover, the results of interactions derived from complex mutational patterns are difficult to predict. Different interpretation algorithms have been developed to facilitate the translation of information obtained in the genotypes to clinicians. Controversy exists, however, regarding the impact of genotypic changes over the activity of many antiretroviral drugs. Based on virologic outcomes, scientific literature, and expert opinion, the Drug Resistance Platform of the Spanish AIDS Research Network (RIS, Red de Investigación en SIDA) has developed over the last years its own interpretation system. Herein, we present the 2009 guidelines, in which special efforts have been made to standardize the criteria for interpreting resistance mutations for compounds within the same drug family and to facilitate the clinical interpretation of HIV-1 resistance genotypes.

Fosamprenavir (GW433908)/ritonavir in HIV-infected patients: efficacy and safety results from the Spanish Expanded Access Program.

INTRODUCTION: The use of protease inhibitors (PI) has led to a decrease in HIV-1-related mortality and morbidity. The objective of this study was to collect safety data on treatment with fosamprenavir/ritonavir (FPV/r) 700/100mg BID in HIV-infected patients through an expanded access program. PATIENTS AND METHODS: Prospective, multicenter, noncomparative study in HIV-1 infected adults, for whom a regimen containing FPV/r 700/100mg BID was appropriate. RESULTS: A total of 678 patients were included in the intention-to-treat (ITT) and safety population. The on-treatment (OT) population contained 587 patients: 76% male, 98% Caucasian, and median age 41 years. Median CD4 cell count was 351 cells/microL, HIV-RNA was 3 log copies/mL, and 49% of patients were in CDC class C. After 24 weeks of treatment, serum viral load decreased a median of 1.3 log copies/mL and 73% of patients had <400 copies/mL (P<.0001 vs. baseline); 48-week results were similar. CD4 cell count increased a median of 49 and 62 cells/microL at 24 and 48 weeks, respectively. Adverse events (AEs) associated with the study medication occurred in 21% of patients. CONCLUSIONS: Ritonavir-boosted fosamprenavir as part of antiretroviral therapy is a potent, safe treatment in real-life clinical circumstances.