753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study. Intervention Patients were randomized to receive either tenofovir DF (n=299) or stavudine (n=303), with placebo, in combination with lamivudine and efavirenz. Main Outcome Measure Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48. Results In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, −10.4% to 1.5%), exceeding the predefined −10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA Ͻ50 copies/ mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P = .06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n=170] vs +134 mg/dL for stavudine [n=162], PϽ.001), total cholesterol (+30 mg/dL [n=170] vs +58 mg/dL [n=162], PϽ.001), direct lowdensity lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], PϽ.001), and high-density lipoprotein cholesterol (+9 mg/dL [n=168] vs +6 mg/dL [n = 154], P = .003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, PϽ.001). The number of bone fractures and the renal safety profile were similar between the 2 groups. Conclusions Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.

Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.)

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BackgroundThe structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM).Methods and FindingsSequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative.ConclusionsReconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Human blood contains at least 2 subpopulations of antigen-presenting dendritic cells (DCs) that can be differentiated by their expression of CD11c. Myeloid DCs (myDCs), which are CD11c ؉ , trap invading pathogens in the tissues and then migrate to lymphoid tissues where they stimulate pathogenspecific T-cell responses. Plasmacytoid DCs (pcDCs), which are CD11c ؊ , secrete interferon-␣ in response to viral infections. This study reports that in HIV-1 infection there is a progressive depletion of both these DC populations and that this correlates with an increasing HIV-1 plasma virus load. The median numbers of myDCs and pcDCs were 6978/mL and 9299/mL, respectively, in healthy male controls and 2298/mL and 1640/mL, respectively, in patients with more than 10 5 HIV-1 RNA copies/mL. Both DC populations expressed CD4, CCR5, and CXCR4. The findings suggest that loss of DCs in HIV infection may contribute to disease progression.

Risk if ART is deferred is taken from [328]. The predicted 6-month risk if ART is initiated is based on the assumption that the rate with immediate therapy initiation is one-third the rate without therapy initiation. This (probably conservative) value is based on considering evidence from multiple sources, including references [32,[329][330][331][332][333].BHIVA treatment guidelines 569 r 2008 British HIV Association HIV Medicine (2008) 9, 563-608 but high CD4 percentages, but also may support a decision to start therapy earlier in patients with absolute CD4 counts 4350 cells/mL but with low CD4 percentages {e.g. o14%, where Pneumocystis carinii pneumonia (PCP) prophylaxis is indicated [35]; some studies have indicated increased risk of disease progression in patients with CD4 percentages o15-17% [36]}. Patients with a CD4 count 4350 cells/mLAs detailed above, at CD4 counts 4350 cells/mL, multiple cohort studies have suggested that there might be benefits to ART. This is supported by data from the substudy of patients not on therapy at entry to the SMART study [32]. Some of the previous concerns about earlier initiation of therapy have been reduced because of the availability of simpler, less toxic and better tolerated antiretroviral regimens, improved pharmacokinetic profiles and increasing options after virological failure. For the majority of patients, the absolute risk of deferring therapy until the CD4 count is o350 cells/mL is likely to be low, but in a subgroup at particularly high risk of clinical events that may be preventable by ART, this is not the case. For all these reasons, in a small number of patients, treatment may be started or considered before the CD4 count is below 350 cells/mL, including the following: AIDS diagnosis (e.g. Kaposi's sarcoma); any HIV-related comorbidity; hepatitis B infection, where treatment of hepatitis B is indicated (see hepatitis guidelines); hepatitis C infection in some cases, where treatment for hepatitis is deferred; low CD4 percentage (e.g. o14%, where PCP prophylaxis would be indicated); established CVD or a very high risk of cardiovascular events (e.g. Framingham risk of CVD 420% over 10 years).Additionally, it is likely that successful antiretroviral treatment, by reducing viral load, reduces infectivity irrespective of the current CD4 cell count, and this may be taken into account in deciding on the timing of starting treatment, particularly in discordant couples where the infected partner has a high viral load. This is likely to be an issue in a very small number of patients, and it must be stressed that antiretroviral treatment in this context would be an adjunct rather than an alternative to safer sex.In patients who do not have an AIDS diagnosis or coinfection with hepatitis B or C virus, and whose CD4 counts are above 500 cells/mL, the benefits of starting therapy remain unclear, the risk of deferring therapy is low, and we recommend that they consider enrolment in the START study, where this is an option. ComorbiditiesWhilst it has been clearly shown that...