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Concept: Tenofovir

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Background Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. Methods We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. Results Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). Conclusions The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472 .).

Concepts: Antiretroviral drug, HIV, AIDS, Sexual intercourse, Oral sex, Tenofovir, Sexually transmitted disease, Human sexual behavior

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Background Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. Methods We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. Conclusions Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656 .).

Concepts: Antiretroviral drug, HIV, AIDS, Hepatitis C, Tenofovir, Emtricitabine, Gilead Sciences, Hepatitis C virus

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Daily oral preexposure prophylaxis (PrEP) using the antiretroviral tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC-TDF) reduces the risk for HIV-1 acquisition. Tenofovir has in vitro activity against herpes simplex virus type 2 (HSV-2).

Concepts: Antiretroviral drug, HIV, Efavirenz, Reverse transcriptase inhibitor, Virus, Herpes simplex, Tenofovir, Gilead Sciences

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Antiretroviral-based HIV-1 prevention strategies - including antiretroviral treatment (ART) to reduce the infectiousness of individuals with HIV-1 and oral and topical pre-exposure prophylaxis (PrEP) for uninfected individuals to prevent HIV-1 acquisition - are the most promising new approaches for decreasing HIV-1 spread. Observational studies among HIV-1 serodiscordant couples have associated ART initiation with a reduction in HIV-1 transmission risk of 80-92%, and a recent randomized trial demonstrated that earlier initiation of ART (that is, at CD4(+) T-cell counts between 350 and 550 cells/mm(3)), in the context of virological monitoring and adherence support, resulted in a 96% reduction in HIV-1 transmission. A number of ongoing and recently-completed clinical trials have assessed the efficacy of PrEP for HIV-1 prevention as pericoitally administered or daily-administered 1% tenofovir gel and daily oral tenofovir disoproxil fumarate (TDF) and combination emtricitabine (FTC)/TDF. Completed studies have demonstrated HIV-1 protection efficacies ranging from 39% to 75%. However, two trials in African women have shown no HIV-1 protection with TDF and FTC/TDF PrEP; the reasons for lack of efficacy in those trials are being investigated. Adherence is likely the key to efficacy of antiretrovirals for HIV-1 prevention, both as ART and PrEP. Critical unanswered questions for successful delivery of antiretroviral-based HIV-1 prevention include how to target ART and PrEP to realize maximum population benefits, whether HIV-1-infected individuals at earlier stages of infection would accept ART to reduce their risk for transmitting HIV-1 and whether highest-risk HIV-1-negative persons would use PrEP, and whether high adherence could be sustained to achieve high effectiveness.

Concepts: Antiretroviral drug, HIV, AIDS, Efavirenz, Reverse transcriptase inhibitor, Tenofovir, Emtricitabine, Gilead Sciences

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Next-generation therapies for chronic hepatitis B virus (HBV) infection will involve combinations of established and/or experimental drugs. The current study investigated the in vitro and in vivo efficacy of tenofovir disoproxil fumarate (TDF) and/or emtricitabine [(-)-FTC] alone and in combination therapy for HBV infection utilizing the HepAD38 system (human hepatoblastoma cells transfected with HBV). Cellular pharmacology studies demonstrated increased levels of (-)-FTC triphosphate with coincubation of increasing concentrations of TDF, while (-)-FTC had no effect on intracellular tenofovir (TFV) diphosphate levels. Quantification of extracellular HBV by real-time PCR from hepatocytes demonstrated the anti-HBV activity with TDF, (-)-FTC, and their combination. Combination of (-)-FTC with TDF or TFV (ratio, 1:1) had a weighted average combination index of 0.7 for both combination sets, indicating synergistic antiviral effects. No cytotoxic effects were observed with any regimens. Using an in vivo murine model which develops robust HBV viremia in nude mice subcutaneously injected with HepAD38 cells, TDF (33 to 300 mg/kg of body weight/day) suppressed virus replication for up to 10 days posttreatment. At 300 mg/kg/day, (-)-FTC strongly suppressed virus titers to up to 14 days posttreatment. Combination therapy (33 mg/kg/day each drug) sustained suppression of virus titer/ml serum (<1 log(10) unit from pretreatment levels) at 14 days posttreatment, while single-drug treatments yielded virus titers 1.5 to 2 log units above the initial virus titers. There was no difference in mean alanine aminotransferase values or mean wet tumor weights for any of the groups, suggesting a lack of drug toxicity. TDF-(-)-FTC combination therapy provides more effective HBV suppression than therapy with each drug alone.

Concepts: Antiretroviral drug, Cirrhosis, Hepatitis, Hepatitis C, Hepatitis B, Tenofovir, Emtricitabine, Gilead Sciences

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QUESTION Does preexposure prophylaxis (PrEP) with antiviral medication for uninfected partners prevent HIV-1 transmission in serodiscordant heterosexual couples? METHODS DESIGN Randomized placebo-controlled trial (Partners Preexposure Prophylaxis [PrEP] Study). ClinicalTrials.gov NCT00557245. ALLOCATION {Concealed*}.† BLINDING Blinded† (participants, clinicians, data collectors, and outcome assessors). FOLLOW-UP PERIOD 36 months (placebo treatment stopped early for apparent benefit). SETTING 9 sites in Kenya and Uganda. PATIENTS 4758 HIV-1 seronegative partners with HIV-infected partners (heterosexual couples) ≥ 18 years of age (62% of HIV-1-negative partners were men, 97% of couples were married). Seropositive partners had CD4 cell counts ≥ 250 cells/mm3 and were not receiving or meeting local guidelines for antiretroviral therapy at enrollment. Seronegative partners had normal renal function (creatinine clearance ≥ 60 mL/min, and serum creatinine ≤ 1.3 mg/dL for men and ≤ 1.1 mg/dL for women) and were not pregnant, breastfeeding, or infected with hepatitis B virus. INTERVENTION Once-daily oral tenofovir disoproxil fumarate, 300 mg (TDF) (n = 1589); TDF, 300 mg, plus emtricitabine, 200 mg (TDF-FTC) (n = 1583); or placebo (n = 1586). All participants received standard comprehensive HIV-1 prevention services. OUTCOME Primary outcome was HIV-1 infection. Other outcomes included adverse events and death. PATIENT FOLLOW-UP 99.5% (modified intention-to-treat analysis excluding participants with HIV-1 RNA detected later by polymerase chain reaction assays in plasma taken at enrollment). MAIN RESULTS 82 partners became infected with HIV-1 during the study. Both TDF and TDF-FTC reduced risk for HIV-1 transmission compared with placebo (Table). TDF and TDF-FTC groups did not differ (P = 0.23). Groups did not differ for adverse events or death (P > 0.24 for all). CONCLUSION Preexposure prophylaxis with oral antiretroviral tenofovir disoproxil fumarate (TDF) and TDF plus emtricitabine reduced transmission of HIV-1 to seronegative partners in serodiscordant heterosexual couples.Tenofovir disoproxil fumarate (TDF), TDF plus emtricitabine (TDF-FTC), or placebo for prevention of HIV-1 transmission to seronegative partners‡OutcomeEvent ratesAt 36 moTDFTDF-FTCPlaceboRRR (95% CI)NNT (CI)HIV-1 transmission to the uninfected partner1.1%3.3%67% (44 to 81)46 (31 to 82)0.8%3.3%75% (55 to 86)41 (29 to 66)‡Abbreviations defined in Glossary. RRR, NNT, and CI calculated from event rates in article. Results for modified intention-to-treat population of 4733 couples.

Concepts: Antiretroviral drug, HIV, AIDS, Efavirenz, Reverse transcriptase inhibitor, Reverse transcriptase, Hepatitis B, Tenofovir

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& Aims: A recent study compared the efficacy of tenofovir disoproxil fumarate (TDF) vs the combination of emtricitabine and TDF (FTC/TDF) in patients with lamivudine-resistant (LAM-R) chronic hepatitis B, treated for as long as 96 weeks. We report findings from resistance analyses conducted for this study.

Concepts: Antiretroviral drug, Hepatitis, Hepatitis B, Tenofovir

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The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings.

Concepts: Antiretroviral drug, HIV, AIDS, Efavirenz, Protease inhibitor, Reverse transcriptase inhibitor, Viral load, Tenofovir

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We characterized the relative fitness of multiple nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) resistant HIV-1 variants in the presence of etravirine (ETV), rilpivirine (RPV) and/or the nucleoside RT inhibitor emtricitabine (FTC) by simultaneous competitive culture and 454 deep-sequencing. The E138A substitution, typically associated with decreased virologic responses to ETV and RPV containing regimens, confers a clear fitness advantage to the virus in the presence of FTC and decreases FTC susceptibility 4.7-fold.

Concepts: HIV, Reverse transcriptase inhibitor, DNA, Reverse transcriptase, Tenofovir, Zidovudine

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Tenofovir disoproxil fumarate (TDF) -containing regimens have been associated with nephrotoxicity and hypophosphatemia in HIV-infected patients. The objective of this study was to assess the possible risk factors for hypophosphatemia and evaluate the relationship between fractional excretion of filtered phosphate (FePi) and hypophosphatemia in TDF users.

Concepts: Tenofovir