Katya Corado

Emtricitabine + tenofovir alafenamide for the treatment of HIV

ABSTRACT Introduction: Tenofovir alafenamide is a new oral prodrug of tenofovir resulting in relatively low plasma levels and rapid uptake into peripheral blood mononuclear cells in its active form. The United States Food and Drug Administration has now approved this drug coformulated with elvitegravir/cobicistat/emtricitabine, rilpivirine/emtricitabine and emtricitabine. United States guidelines now list this formulation as one of the preferred components of a variety of antiretroviral regimens, and is included as an alternative in other international guidelines, with the notable exception of the World Health Organization, mostly due to limited availability. Areas covered: This review covers pre-clinical and clinical data searched through PubMed up to August 2016. Expert opinion: Tenofovir alafenamide is effective as part of an antiretroviral regimen. There is also compelling data that it has less adverse effects on bone mineral density and possibly kidneys than tenofovir disoproxil fumarate. Although approved for use in those with estimated glomerular filtration rates as low as 30 mL/min, data is somewhat limited in this group. While there are few reasons to not use tenofovir alafenamide as a substitute for tenofovir disoproxil fumarate, the former should not be used with rifamycins, is not yet recommended in pregnancy and needs to be studied further before it can be considered as part of a pre-exposure prophylaxis regimen.

Condomless Sex With Virologically Suppressed HIV-Infected Individuals: How Safe Is It?

The use of antiretroviral therapy (ART) across the globe has had a profound influence on the natural history of HIV infection. Although the pandemic continues to spread, one of the greatest advances in prevention since the use of ART in pregnancy to avoid vertical transmission was the recognition that the same treatment prevents horizontal transmission. Many cohorts have suggested this benefit,1,2 findings that in part led to the Swiss Commission statement in 2008 that HIV-infected individuals who have had suppressed plasma HIV RNA load for longer than 6 months and who do not have sexually transmitted infections (STIs) were not sexually infectious.3 Although the statement was controversial at the time, the cohort data were compelling, and there have been very few case reports of an HIV transmission event from a virologically suppressed person and no events identified in a systemic review of patients with suppressed plasma HIV RNA load in cohort studies and randomized controlled trials.4 The results of a large randomized clinical trial of early vs deferred ART in the HIV-infected partner in serodiscordant couples, the HIV Prevention Trials Network (HPTN) 052, further demonstrated the low risk of transmission from HIVinfected patients receiving ART. This study was stopped prematurely when the investigators found that early therapy was associated with a 96% reduction in risk of transmission to the uninfected partner.5 Final study results showed a 93% reduced risk of HIV transmission and no transmission events from those who were virologically suppressed while taking ART.6 Although these findings supported the potential public health benefits of ART, the study did not fully address the question as to whether patients with plasma HIV RNA suppression can have condomless sex without concern for transmitting HIV. The study primarily included heterosexual couples, making it impossible to extrapolate results to other groups, such as men who have sex with men (MSM). In addition, the study design included a comprehensive prevention package that included regular counseling about safe sex, testing for and treatment of STIs, and frequent testing for HIV, along with provision of condoms to all study participants and encouragement for their use. In this issue of JAMA, Rodger and colleagues7 report data from the PARTNER study, a prospective, observational cohort of 1166 serodiscordant couples with the HIV-infected partner receiving ART and having plasma HIV RNA levels less than 200 copies/mL. These couples were recruited from 75 European sites between September 2010 and May 2014 and included only those who reported routine engagement in condomless sex. The analyses included 888 couples with 1238 couple-years of follow-up (median, 1.3 years); 340 MSM and 548 heterosexual couples (269 HIV-infected male partners and 279 HIV-infected female partners). At study entry, the couples reported condomless sex for a median of 2 years (interquartile range, 0.5-6.3 years); during the course of follow-up, the couples reported approximately 40 000 condomless sex acts. The main finding was that 11 uninfected partners became infected with HIV, 10 among MSM and 1 among the heterosexual partners. Notably, none of these infections proved to involve viruses phylogenetically linked to the HIV-infected study partner. As a result, the authors concluded that there were no transmission events from virologically suppressed HIV-infected participants to their uninfected partners. The PARTNER study by Rodger et al7 addresses some of the important limitations of HPTN 052. For example, this cohort included MSM and demonstrated no within-couple HIV transmission events within the group. In addition, unlike HPTN 052, in which ART was used as an adjunct to a strong safe sex message, the PARTNER study enrolled individuals who admitted to primarily engaging in condomless sex with their partners. However, the biology of HIV transmission and human behavior is complicated, and it is inevitable that enrollment into a study, even a cohort study, has a potential influence on these factors. The PARTNER study also has several limitations that must be considered in its interpretation and potential clinical application. First, despite the impressive effort to enroll a large and diverse group of individuals, the study had limited power. The authors note that despite a rate of 0 for withincouple HIV transmission, the upper 95% confidence limit for within-couple transmissions per 100 eligible couple-years of follow-up for heterosexuals was 0.97 for the male HIVpositive/female HIV-negative couple group, 0.88 for the female HIV-positive/male HIV-negative couple group, and 0.84 for the MSM couple group. For persons engaging in receptive anal sex with ejaculation inside the uninfected partner, the upper 95% confidence limit for within-couple HIV transmission was 2.7 per 100 couple-years of follow-up; however, this estimate was based on relatively small numbers, because only 45% of the MSM group reported this type Related article page 171 Opinion

Randomized Controlled Trial of Daily Text Messages to Support Adherence to Preexposure Prophylaxis in Individuals at Risk for Human Immunodeficiency Virus: The TAPIR Study

Background Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP). Methods Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours). Results Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05). Conclusions Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence. Clinical Trials Registration NCT01761643.

Recent HIV Risk Behavior and Partnership Type Predict PrEP Adherence in Men who have Sex with Men

Abstract Background Individuals engaging in higher risk behavior are often more adherent to PrEP but it is unclear if partnership type itself affects PrEP adherence. We examined the effect of recent HIV risk behaviors and partnership type on PrEP adherence in men who have sex with men (MSM) taking PrEP. Methods CCTG 595 is a 48-week PrEP demonstration study of 398 HIV− at-risk MSM. At baseline and week 48, HIV risk score was estimated as the probability of seroconversion over the next year based on number of condomless anal sex acts with HIV+/unknown partners in the last month and any STI diagnosed at study visit. HIV risk score was categorized as low (<0.12), moderate (0.12−0.59) and high (>0.59) risk based on population seroconversion probabilities. Partnership type was assigned as no/single HIV− partner, single HIV+ partner, or multiple partners of any serostatus in the past 3 months. PrEP adherence was estimated by intracellular tenofovir-diphosphate (TFV-DP) levels as a continuous variable at week 48. Statistical methods included McNemar’s test, Wilcoxon rank-sum test, and linear regression model where appropriate. Results Of 313 MSM who completed week 48, there was no significant change in HIV risk category from baseline to week 48 (low: 44 to 42%; moderate: 27 to 24%; high: 28 to 34%; P = 0.25). There was a significant change in partnership type, with the proportion of those with no or single HIV− partnerships increasing (1 to 9%, P < 0.001). In univariate analysis, moderate and high-risk groups had higher TFV-DP levels than the low-risk group at week 48 (P = 0.018). Participants with no/single HIV− partner had significantly lower TFV-DP levels than those with one HIV+ partner or multiple partners (P = 0.007). In a multivariable linear regression model, only low-risk partnerships remained significant where no/single HIV− partnerships were associated with lower TFV-DP levels (mean difference = −344fmol/punch [−617, −71], P = 0.014). Conclusion Although there was a shift in partnership type towards lower risk partnerships, objective HIV risk behavior remained stable over time. Individuals with higher HIV risk behaviors and risk partnerships had higher TFV-DP levels suggesting maintained strong motivation for PrEP adherence. Thus, recent sexual risk behavior and partnership type may be important predictors of PrEP adherence in MSM. Disclosures All authors: No reported disclosures.

Effect of rectal douching/enema on rectal gonorrhoea and chlamydia among a cohort of men who have sex with men on HIV pre-exposure prophylaxis

Objectives Rectal douching/enema (RD) is a common practice among men who have sex with men (MSM) in preparation for sex. RD can break down the rectal mucosal barrier and potentially affect the rectal microbiome. The objective of this study was to understand if RD is associated with acquiring rectal infections (RI) with rectal gonorrhoea (NG) and/or chlamydia (CT). Methods From 2013 to 2015, 395 adult HIV-uninfected MSM were enrolled in a randomised controlled study for pre-exposure prophylaxis (PrEP) adherence with routine sexual risk survey and testing. Using data from this cohort, baseline differences by RI were assessed using Pearson’s χ² and Wilcoxon-Mann-Whitney test. Association between RD and RI was modelled using multivariable logistic regression adjusted for potential confounders (sexual behaviour, substance use and age) selected a priori. Effect modification by number of male partners and sensitivity analysis to rule out reverse causality were also conducted. Results Of 395 participants, 261 (66%) performed RD and 133 (33%) had at least one NG/CT RI over 48 weeks. Number of condomless anal receptive sex (med: 4, p<0.001), male partners (med:6, p<0.001) and substance use (any of methamphetamine/hallucinogens/dissociative/poppers) (p<0.001) were associated with increased odds of RI. Controlling for potential confounders, odds of prevalent RI were 3.59 (p<0.001, 95% CI 1.90 to 6.78) and incident RI 3.87 (p=0.001, 95% CI 1.78 to 8.39) when douching weekly or more compared with not douching. MSM with more than six male partners had 5.34 (p=0.002, 95% CI 1.87 to 15.31) increased odds of RI when douching weekly or more compared with not douching. Conclusion Rectal hygiene with RD is a common practice (66%) among HIV-uninfected MSM on PrEP in this study, which increases the odds of acquiring rectal NG and/or CT independent of sexual risk behaviour, substance use and other factors. This suggests interventional approaches targeting rectal hygiene products and practices could reduce sexually transmitted infections.

Next generation fixed dose combination pharmacotherapies for treating HIV

ABSTRACT Introduction: Treatment options for patients with HIV-1 infection have grown over the past two decades to include multiple fixed-dose combination pharmacotherapies that have greatly simplified administration of antiretroviral therapy (ART) for both patients and providers. Effective virologic control can often be achieved with once-daily use of a single-tablet regimen. Over the past three years, ART drug development has focused on the next generation of fixed-dose combinations for initial and maintenance therapy with improved efficacy, safety and tolerability. Areas covered: This review covers pre-clinical and clinical data searched through PubMed and presented at major conferences through November 2017. Expert opinion: Currently available single-tablet regimens have clinical limitations related to adverse event profiles, drug-drug and drug-food interactions and variable barriers to resistance. Anticipated advances in ART fixed-dose combinations promise combinations of current multiple tablet regimens into single tablets, as well as combinations with novel drugs with improved safety and tolerability. The traditional dogma of effective ART containing at least three active antiretroviral drugs is being challenged by promising data to support efficacy of certain regimens containing two drugs. Implementation of next generation ART will bring to light issues of clinical preference and cost-effectiveness as patents of existing drugs expire and more generic formulations become available.

Tenofovir Disoproxil Fumarate-Associated Fanconi Syndrome in an Human Immunodeficiency Virus (HIV)-Uninfected Man Receiving HIV Pre-Exposure Prophylaxis

Tenofovir disoproxil fumarate (TDF) has been used worldwide in antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients since being approved by the US Food and Drug Administration in 2001. Tenofovir disoproxil fumarate can cause renal tubular dysfunction and reduced renal function [1]. In its fully developed form, TDF renal dysfunction is associated with hypophosphatemia, renal phosphate wasting, and other features of Fanconi syndrome [1]. Cases of TDF-associated Fanconi syndrome have been reported predominantly among patients with HIV infection [1]. There has been no excess risk of renal tubular toxicity with TDF-emtricitabine (TDF-FTC) detected in large, placebo-controlled trials of HIV pre-exposure prophylaxis (PrEP) [2, 3]. One other well documented likely Fanconi syndrome has been reported in an online supplement to the latter paper [3]. In this study, we report an additional case of this previously described phenomenon.