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OBJECTIVE: To evaluate the effects of HIV pre-exposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health. DESIGN: The Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence. METHODS: We compared estimated glomerular filtration rate calculated using serum creatinine (eGFRcr), serum cystatin C (eGFRcys), and in combination (eGFRcr-cys), and a panel of 14 urine biomarkers reflecting kidney tubular health before and six months after PrEP initiation. RESULTS: At baseline, mean eGFRcr, eGFRcys, and eGFRcr-cys were 108.3, 107.0, and 111.1 mL/min/1.73m(2), respectively. Six months after PrEP initiation, eGFRcr declined by −4.0% (95% CI: −5.7% to −2.4%), eGFRcys declined by −3.3% (95% CI: −8.3% to 1.9%), and eGFRcr-cys declined by −4.1% (95% CI: −7.5% to −0.7%). From the urine biomarker panel, a1-microglobulin and P2-microglobulin increased by 22.7% (95% CI: 11.8% to 34.7%) and 14.1% (95% CI: −6.1% to 38.6%), whereas chitinase-3-like 1 protein and monocyte chemoattractant protein-1 decreased by −37.7% (95% CI: −53.0% to −17.3%) and −15.6% (95% CI: −31.6% to 4.2%), respectively. Ten of the 14 urine biomarkers, including albumin, had estimated changes of less than 12% with wide confidence intervals. CONCLUSION: Six months of PrEP with TDF/FTC was associated with decreases in eGFRcr and eGFRcys. We also observed for the first time changes in four of 14 urine biomarkers reflecting kidney tubular health. These findings demonstrate that PrEP has direct effects on eGFR and the proximal tubule.

OBJECTIVE We examined the relationship between urine tenofovir (TFV) levels measured with a novel immunoassay, which permits point-of-care testing, with HIV seroconversion and objective adherence metrics in a large preexposure prophylaxis (PrEP) demonstration project. DESIGN Secondary analysis of stored specimens from an open-label PrEP cohort study. METHODS We examined the association between undetectable urine TFV levels and HIV seroconversion in iPrEx open-label extension using generalized estimating equations. We examined rank correlations between levels of TFV and emtricitabine in urine, dried blood spots (DBS), and hair and determined the sensitivity and specificity of undetectable urine TFV for predicting dosing cut-offs in DBS. RESULTS The median urinary TFV level was 15 000 ng/ml in those who remained HIV-negative (n = 105; interquartile range: 1000-45 000); 5500 in those who eventually seroconverted (n = 11; interquartile range: 1000-12 500); and all were undetectable at seroconversion (n = 9; P

Supplemental Digital Content is available in the text, Objectives: To review the main factors influencing the costs of nondaily oral preexposure prophylaxis (PrEP) with tenofovir (±emtricitabine). To estimate the cost reductions possible with nondaily PrEP compared with daily PrEP for different populations (MSM and heterosexual populations). Design: Systematic review and data triangulation. Methods: We estimated the required number of tablets/person/week for dosing regimens used in the HPTN 067/ADAPT (daily/time-driven/event-driven) and IPERGAY (on-demand) trials for different patterns of sexual intercourse. Using trial data, and behavioural and cost data obtained through systematic literature reviews, we estimated cost savings resulting from tablet reductions for nondaily versus daily oral PrEP, assuming 100% adherence. Results: Among different populations being prioritized for PrEP, the median reported number of days of sexual activity varied between 0 and 2 days/week (0–1.5 days/week for MSM, 1–2 days/week for heterosexual populations). With 100% adherence and two or fewer sex-days/week, HPTN 067/ADAPT nondaily regimens reduced the number of tablets/week by more than 40% compared with daily PrEP. PrEP program costs were reduced the most in settings with high drug costs, for example, by 66–69% with event-driven PrEP for French/US populations reporting on average one sex-day/week. Conclusion: Nondaily oral PrEP could lower costs substantially (>50%) compared with daily PrEP, particularly in high-income countries. Adherence and efficacy data are needed to determine cost-effectiveness.

Objective: Preexposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes. Design: Rigorous systematic review and meta-analysis. Methods: A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis. Results: Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared with placebo. Trials with PrEP use more than 70% demonstrated the highest PrEP effectiveness (risk ratio = 0.30, 95% confidence interval: 0.21–0.45, P

Objective: HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs. Methods: We recruited donor partners of persons who presented with acute or recent (

Objectives: Primary, or transmitted, drug resistance is common among treatment naive patients recently infected with HIV-1, and impairs response to anti-retroviral therapy. We previously observed that patients with secondary resistance (developed in response to anti-retroviral treatment) who chose to stop an anti-retroviral regimen experience rapid overgrowth of drug resistant viruses by wild-type virus of higher pol replication capacity. We sought to determine if primary drug resistance would be lost at a rapid rate, and viral pol replication capacity would increase, in the absence of treatment. Methods: We tracked drug resistance phenotype, genotype, viral pol replication capacity (single cycle recombinant assay incorporating a segment of the patient pol gene [pal RCl), plasma HIV-1 RNA, and CD4 T cell counts in the absence of treatment among patients in early HIV-1 infection. Results: Six of 22 patients had evidence of primary drug resistance to at least one class of drug; three resistant to protease inhibitors, three resistant to non-nucleoside reverse transcriptase inhibitors, and four resistant to nucleoside reverse transcriptase inhibitors. All six patients maintained evidence of drug resistance for the period of observation. Among patients with baseline primary drug resistance pol RC did not increase over time. Conclusion: The selection environment of early infection is determined by immune pressure, and stochastic events, not viral pol replication capacity. In contrast to secondary resistant infections that are rapidly overgrown when therapy is stopped, primary drug resistance persists over time. Surveillance and clinical detection of primary resistance is feasible in the first year of infection.

Objective: Little is known about the degree to which widespread use of antiretroviral therapy in a community reduces uninfected individuals’ risk of acquiring HIV. We estimated the degree to which the probability of HIV infection from an infected partner (the infectivity) declined following the introduction of highly active antiretroviral therapy (HAART) in San Francisco. Design: Homosexual men from the San Francisco Young Men’s Health Study, who were initially uninfected with HIV, were asked about sexual practices, and tested for HIV antibodies at each of four follow-up visits during a 6-year period spanning the advent of widespread use of HAART (1994 to 1999). Methods: We estimated the infectivity of HIV (per-partnership probability of transmission from an infected partner) using a probabilistic risk model based on observed incident infections and self-reported sexual risk behavior, and tested the hypothesis that infectivity was the same before and after HAART was introduced. Results: A total of 534 homosexual men were evaluated. Decreasing trends in HIV seroincidence were observed despite increases in reported number of unprotected receptive anal intercourse partners. Conservatively assuming a constant prevalence of HIV infection between 1994 and 1999, HIV infectivity decreased from 0.120 prior to widespread use of HAART, to 0.048 after the widespread use of HAART – a decline of 60% (P ¼ 0.028). Conclusions: Use of HAART by infected persons in a community appears to reduce their infectiousness and therefore may provide an important HIV prevention tool.

Objective: Among treated patients with drug-resistant viremia, structured treatment interruptions often result in the re-emergence of drug-susceptible HIV-1. Theoretically, this may allow for a more durable response to salvage therapy. We therefore studied the long-term treatment outcome to antiretroviral therapy in a cohort of patients who had previously interrupted therapy, focusing on the determinants of treatment success versus failure. Design: A prospective observational study of the response to antiretroviral therapy in patients resuming therapy after a treatment interruption. Virological and immunological studies were performed every month for 3 months and then every 3 months. Results: Twenty-four patients underwent a structured treatment interruption and d therapy after a variable period of time (median 20 weeks). The median duration of treatment after the treatment interruption was 109 weeks. A transient virological response was observed in all patients who resumed a regimen containing no drug to which their pre-interruption virus was fully susceptible. Virus isolated during virological failure was genotypically and phenotypically identical to the pre-interruption virus, exhibited reduced replicative capacity, and replicated in vivo at levels similar to the pre-interruption baseline. In contrast, durable viral suppression (< 200 copies/ml) was observed in patients who initiated a regimen containing only one drug to which their pre-interruption virus was fully susceptible. Despite viral suppression, the pre-interruption drug-resistant virus population remained detectable in two patients. Conclusion: Although drug-resistant HIV-1 persists at low levels during and after the interruption of therapy, durable suppression of this virus population may be achieved with a combination regimen containing only one fully active agent.

Objective To determine whether treatment with growth hormone (GH) enhances thymopoiesis in individuals infected with HIV-1. Methods Five HIV-1-infected adults were treated with GH for 6-12 months in a prospective open-label study. Immunological analyses were performed before GH treatment and repeated at 3 month intervals after GH initiation. Thymic mass was analysed using computed tomography with quantitative density and volume analysis. Analysis of circulating lymphocytes, including naive and memory T cell subsets, was performed using multiparameter flow cytometry. Results GH treatment was associated with a marked increase in thymic mass in all GH recipients. Circulating naive CD4 T cells also increased significantly in all patients during GH therapy, suggesting an enhancement of thymopoiesis. Conclusion GH has significant effects on the human immune system, including the reversal of thymic atrophy in HIV-1-infected adults. De-novo T cell production may thus be inducible in immunodeficient adults.

OBJECTIVE Structured antiretroviral treatment interruption (STI) has been advocated as a therapeutic strategy for HIV-1 infection. We report initial observations of cerebrospinal fluid (CSF) HIV-1 infection in five patients undergoing serial lumbar punctures (LPs) during STI undertaken following virological failure. DESIGN AND METHODS In this prospective observational study we quantified HIV-1 RNA concentrations and assessed both phenotypic drug susceptibility profiles and genotypic antiviral drug resistance mutations in CSF and plasma during the period of treatment interruption. CSF white blood cells were also counted, and patients' neurological status monitored. RESULTS In four of the patients, CSF HIV-1 concentration increased more rapidly than that of the plasma, with consequent reduction in the ratio between plasma and CSF viral loads (pVL : cVL). Three individuals developed robust, though asymptomatic CSF lymphocytic pleocytosis. In all patients the predominant HIV-1 quasispecies shifted simultaneously in CSF and plasma from a drug-resistant to a more drug-susceptible phenotype with identical and simultaneous changes in genotypes associated with drug resistance. CONCLUSIONS STI may be accompanied by previously unrecognized changes in tissue viral exposures and lymphocyte traffic. Hence, despite 'virological failure' as evidenced by persistent plasma viremia, ongoing antiretroviral treatment prior to its interruption appeared to suppress CSF HIV-1 infection (indeed more effectively than that of plasma) and restrain lymphocyte traffic into the CSF. Simultaneous change of resistance mutations in CSF and plasma was likely due to re-emergence and overgrowth of pre-existing strains with ready exchange of virus between these two compartments, either facilitated by or provoking a local CSF lymphocytosis.

Objectives: To compare the kinetics and magnitude of HIV-1 RNA responses to antiretroviral therapy (ART) in the cerebrospinal fluid (CSF) and plasma. Design: Repeated lumbar punctures (LPs) were performed after the initiation or change in ART in 15 HIV-1-infected subjects, with the focus on two phases of response: an acute phase within the first 11 days, for which crude estimates of viral RNA half-lives and decay rates were derived and CSF:plasma relative decay ratios quantitatively analysed; and a longer-term phase beyond 4 weeks that was descriptively assessed. Results: In 13 subjects studied during the acute phase, the crude HIV-1 RNA half-life was longer (median 2.0 compared with 1.9 days), the decay rate slower (median 0.13 compared with 0.16 log10 copies/day) and, most notably, the variability greater (intraquartile range of half-life 1.8-4.3 compared with 1.7-2.1 days) in the CSF than in the plasma. A slower decay in the CSF correlated with lower initial blood CD4 T lymphocyte counts (P=0.001). Seven of 11 subjects studied at 4 weeks or later, including some with slower acute-phase CSF responses, showed greater or more durable viral suppression in the CSF. Conclusion: Divergent acute-phase viral kinetics in the CSF and plasma, and proportionally greater long-term decrements in CSF HIV-1 RNA in slow early-responders or poor overall plasma responders indicate variable compartmentalization of CSF infection, consistent with a model of two prototypes of CSF infection: short-lived, transitory infection that predominates in early HIV-1 infection and longer-lived, more autonomous CSF infection predominating in late HIV-1 infection. Additional studies will be needed to define more precisely the acute and longer-term CSF kinetics in different clinical settings and to assess this model.

Objective: To determine the HIV RNA and CD4 cell response to both initial and salvage therapy with protease inhibitor-based therapy, and to examine the relationship between the virological response and pre-therapy characteristics. Design: Observational cohort. Setting: University-based public hospital AIDS clinic. Patients: HIV-infected adults who received at least 16 continuous weeks' therapy with a potent protease inhibitor (indinavir, ritonavir or nelfinavir)-based regimen, and who have had at least 48 weeks of follow-up. Main outcome measures: Plasma HIV RNA and CD4 cell count response at week 48 of therapy for patients receiving their first protease inhibitor-containing regimen, and at week 24 of therapy with a salvage regimen. Results: Of the 337 patients analysed, 170 (50.2%) had a successful outcome (HIV RNA < 500 copies/ml after 48 weeks of treatment). Independent predictors of virological failure were higher baseline HIV RNA level, lower baseline CD4 cell count and failure to initiate at least one new nucleoside analog simultaneously at the time protease inhibitor therapy was initiated. The risk of failure increased incrementally across most HIV RNA and CD4 cell strata, with significant increases as the HIV RNA increased above 4.5 log 10 copies/ml and the CD4 cell count fell below 100 cells/mm 3 (P < 0.01). ). The CD4 cell count remained above baseline to week 48 in most patients, regardless of the HIV RNA response. Of the 99 patients who experienced virological failure and switched to a salvage regimen, only 22 (22%) achieved an undetectable HIV RNA level 24 weeks after initiating salvage therapy. Independent predictors of failure with salvage therapy included an HIV RNA greater than 4.0 log 10 RNA copies/m at the time of the switch and failure to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) in the salvage regimen. Conclusion: Failure of potent protease inhibitor therapy to suppress HIV RNA levels below detectable levels is common in clinical practice, and can often be explained by their suboptimal use. CD4 T cell counts remain above baseline for at least one year in most patients experiencing virological failure. Successful salvage therapy, which was uncommon, was associated with a low plasma HIV RNA at the time of the switch and the use of a new class of antiretroviral agents (NNRTI) in the salvage regimen.

Objective: To evaluate the virologic activity of a ritonavir plus saquinavir-containing regimen in patients who have failed an indinavir or ritonavir-containing regimen. Design: Patients were identified through a retrospective study evaluating the incidence of indinavir or ritonavir failure in our clinic. Patients: Eighteen patients failing indinavir or ritonavir therapy and who switched to a ritonavir-saquinavir-containing regimen were evaluated. Indinavir or ritonavir failure was defined as a plasma viral load >1500 copies/ml (branched DNA) after 16 weeks of continuous therapy. Interventions: All patients switched to ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) and received concurrent therapy with two nucleoside reverse transcriptase inhibitors (NRTI). Twelve of the 18 patients modified their NRTI regimen at the time ritonavir-saquinavir was initiated. Outcome measures: Plasma viral load was monitored using a branched DNA assay. Genotypic analysis was performed using a point mutation differential hybridization technique, and was confirmed with direct sequencing. Results: Fourteen out of 18 patients completed at least 24 weeks of therapy; the remaining four patients discontinued therapy after week 12 due to a lack of virologic response or intolerance. Plasma viral load decreased a median 1.4 log 10 after 4 weeks of treatment with ritonavir-saquinavir. Only four patients had a greater than 0.5 log 10 decrease in viral load after 24 weeks of therapy. In eight out of 10 patients evaluated, the V82A mutation was present at the time of the switch to ritonavir-saquinavir. Viral rebound on ritonavir-saquinavir was associated with the emergence of mutations at amino acids 46, 48, 54 and 90. Conclusion: The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir-saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.