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Summary Background In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov , number NCT02842086 . Findings Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07–0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17–0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78–82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p Interpretation Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding Gilead Sciences.

To discuss the potential role of islatravir (ISL), a novel reverse transcriptase translocation inhibitor, in the treatment and prevention of human immunodeficiency virus type 1 (HIV-1) infection.Islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591) is a long-acting first-in-class nucleoside reverse transcriptase translocation inhibitor with the potential for versatile dosing routes and dosing intervals. It demonstrated robust antiviral activity when dosed once daily and once weekly in HIV-1-infected individuals and SIV-infected rhesus macaques. In clinical trials of ISL in combination with doravirine and lamivudine, daily oral administration resulted in high levels of virologic suppression in HIV-infected individuals. In preclinical studies, ISL dosed orally once-weekly as preexposure prophylaxis (PrEP), protected rhesus macaques against SHIV infection via the mucosal route in the low-dose rectal challenge model. Most recently, data in healthy HIV-1-uninfected individuals demonstrated the feasibility of formulating of ISL as an implant. In these studies, levels of intracellular ISL-triphosphate were consistent with the potential for a once-yearly implantable administration of ISL as PrEP.Islatravir is a promising new agent for both the treatment and prevention of HIV-1 infection.

HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (P = 0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7 = 43%). Two HAND subjects (2/7 = 29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n = 4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on nonsuppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the central nervous system (CNS) can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts. IMPORTANCE Several antiretroviral agents do not efficiently enter the CNS, and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We used single-genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 polymerase genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on nonsuppressive cART, and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.

Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor in development as a long-acting (LA) intramuscular injectable suspension for HIV-1 pre-exposure prophylaxis (PrEP).We report participant outcomes from the phase IIa ECLAIR study related to tolerability, acceptability, and satisfaction of cabotegravir LA.The ECLAIR study (ClinicalTrials.gov identifier, NCT02076178) was a randomized, placebo-controlled study in healthy men not at high risk of acquiring HIV-1. Participants were randomized (5:1) to once-daily oral cabotegravir 30 mg or placebo tablets for 4 weeks, followed by gluteal intramuscular injections of cabotegravir LA 800 mg or saline placebo every 12 weeks. The primary objective was to evaluate the safety of cabotegravir LA over three injection cycles (to Week 41). Secondary objectives assessed the tolerability, satisfaction, and acceptability of cabotegravir LA.Among 115 participants who received injections in the cabotegravir (n = 94) and placebo (n = 21) groups, 93% (n = 87) and 95% (n = 20) completed the injection phase, respectively. Injection intolerability led to withdrawal in 4 participants (4%) receiving cabotegravir LA. The most frequently reported Grade ≥2 adverse event was injection-site pain. Most participants (74% [n = 67]) receiving consecutive injections favored cabotegravir LA vs oral cabotegravir. Most participants were satisfied with cabotegravir LA (75% [n = 64]), were willing to continue (79% [n = 68]), and would recommend (87% [n = 75]) the therapy.While Grade ≥2 injection-site pain was common, most participants reported overall satisfaction with and preference for cabotegravir LA, with few discontinuations due to injection intolerance. These findings support investigation of cabotegravir LA as an alternative to daily oral PrEP regimens.

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and preexposure prophylaxis of HIV-1 infection.EFdA is active against wild-type (EC50 as low as 50 pmol/l) and most highly NRTI-resistant viruses. The active metabolite, EFdA-triphosphate, has been shown to have a prolonged intracellular half-life in human and rhesus (Rh) blood cells. As a result, single drug doses tested in simian immunodeficiency virus mac251-infected Rh macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7-10 days duration. Preclinical studies of EFdA as preexposure prophylaxis in the Rh macaque/simian/human immunodeficiency virus low-dose intrarectal challenge model have shown complete protection when given in clinically relevant doses.EFdA is a novel antiretroviral with activity against both wild-type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer.

Human Immunodeficiency Virus (HIV) is a chronic infection that depletes the immune system of essential components causing those infected to be at risk for multiple life-threatening infections. Worldwide, millions live with this infection, the vast majority attributable to HIV-1. Transmission persists with hundreds of thousands of new infections reported yearly. Implementation of combination antiretroviral therapy (cART) has been effective in improving outcomes and decreasing transmission. Newer co-formulated agents have provided simpler medication regimens, fewer side effects, and, in some cases, a higher barrier to the emergence of medication resistance. Areas covered: Here, we review trials of cabotegravir (CAB) as treatment of HIV-1 infection and its potential use as pre-exposure prophylaxis (PrEP) in high risk individuals, including issues around oral lead in and potential resistance emergence. Expert opinion: CAB is efficacious when used in combination therapy orally or given intramuscularly every 4 to 8 weeks. Its availability in a long-acting injectable formulation (CAB-LA) makes it a valuable, novel drug to treat HIV-1 infection when combined with long-acting injectable rilpivirine (RPV-LA). Moreover, pre-clinical and early Phase 2a studies support its testing as monotherapy as PrEP. Studies are underway comparing the efficacy of every 8 week CAB-LA to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).

Summary Background Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection. Methods We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18–65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178. Findings Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 μg/mL (95% CI 0·237–0·385), 0·331 μg/mL (0·253–0·435), and 0·387 μg/mL (0·296–0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration. Interpretation Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens. Funding ViiV Healthcare.

This study aimed to identify patients' physical and psychosocial experiences of an investigational long-acting injectable PrEP product to aid in the development of patient and provider education materials. Twenty-eight participants of a Phase 2 safety, tolerability, and acceptability study of long-acting integrase inhibitor cabotegravir (CAB-LA) were interviewed on their physical and psychosocial experiences of the injections. Five themes emerged through a framework analysis on these interview transcripts: (1) injection-related pain is highly variable across individuals; (2) pain is more impactful after the injections than during; (3) patient anxiety is critical, but does not determine the experience of injections and decreases over time; (4) intimacy and awkwardness of gluteal injections impacts patients' experiences; (5) patient education and care strategies can mitigate the above factors. These findings can inform further sociobehavioral research within Phase 3 efficacy trials of CAB-LA, as well as patient education and provider guidance for future injectable PrEP products.

Pattern recognition receptors (PRRs) protect against host invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. While microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation during viral infection remain overlooked. In this work, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary structure and its 5’-triphosphate extremity. Further, we found that HIV-1 infection triggers a VPR-dependent downregulation of RNA triphosphatase DUSP11in vitroandin vivo, leading to an increase of Y-RNA 5’-triphosphorylation that enables their immunogenicity. Importantly, we show that altering DUSP11 expression is sufficient to induce a type-I interferon and T cell activation transcriptional program associated with HIV-1 infection. Overall, our work uncovers the critical contribution of endogenous repeat RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.

Upon completion of this chapter, the reader should be able to • Demonstrate and apply knowledge about established and evolving science describing HIV virology, both in the cell and in the host. • Effectively counsel and educate patients and their communities regarding HIV treatment.

Risk of HIV infection is high in Chinese MSM, with an annual HIV incidence ranging from 3.41 to 13.7/100 person-years. Tenofovir-based PrEP is effective in preventing HIV transmission in MSM. This study evaluates the epidemiological impact and cost-effectiveness of implementing PrEP in Chinese MSM over the next two decades. A compartmental model for HIV was used to forecast the impact of PrEP on number of infections, deaths, and disability-adjusted life years (DALY) averted. We also provide an estimate of the incremental cost-effectiveness ratio (ICER) and the cost per DALY averted of the intervention. Without PrEP, there will be 1.1–3.0 million new infections and 0.7–2.3 million HIV-related deaths in the next two decades. Moderate PrEP coverage (50%) would prevent 0.17–0.32 million new HIV infections. At Truvada’s current price in China, daily oral PrEP costs $46,813–52,008 per DALY averted and is not cost-effective; on-demand Truvada reduces ICER to $25,057–27,838 per DALY averted, marginally cost-effective; daily generic tenofovir-based regimens further reduce ICER to $3675–8963, wholly cost-effective. The cost of daily oral Truvada PrEP regimen would need to be reduced by half to achieve cost-effectiveness and realize the public health good of preventing hundreds of thousands of HIV infections among MSM in China.

Adherence challenges with oral pre-exposure prophylaxis have stimulated interest in alternate modes of administration including long-acting injections. We conducted 30 in-depth interviews with 26 male trial participants and 4 clinical providers in a Phase IIa study (ECLAIR) evaluating the use of long-acting cabotegravir (CAB-LA) injections in New York and San Francisco. Interviews exploring attitudes and experiences with CAB-LA were audiotaped, transcribed, and analyzed using thematic content analysis. Despite a high frequency of some level of side effects, almost all participants reported being interested in continuing with CAB-LA, versus a daily oral, due to its convenience and the perceived advantage of not worrying about adhering to pills. Providers reinforced the importance of CAB-LA as a prevention option and the need for guidelines to assist patient decision-making. Further research is needed on the acceptability of CAB-LA among men and women at higher risk for HIV in different settings.

Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants (n = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4+ T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4+ T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV+ subjects indicating promise as an adjuvant for HIV therapeutic vaccines. Trial Registration: www.ClinicalTrials.gov, identifier: NCT02071095.

Background Treatment of HIV-infected men during early hepatitis C virus (HCV) infection with interferon results in a higher cure rate with a shorter duration of treatment than during chronic HCV infection. We recently demonstrated that this phenomenon applied to interferon-free treatment as well, curing most participants with short-course sofosbuvir and ribavirin. Due to the significantly higher potency of the ledipasvir/sofosbuvir (LDV/SOF) combination, we hypothesized that we would be more successful in curing early HCV infections using a shorter course of LDV/SOF than that used for treating chronic HCV infections. Methods We performed a prospective, open-label, consecutive case series study of 8 weeks of LDV/SOF in HIV-infected men with early genotype 1 HCV infection. The primary end point was aviremia at least 12 weeks after completion of treatment. Results We treated 25 HIV-infected men with early sexually acquired HCV infection with 8 weeks of LDV/SOF, and all 25 (100%) were cured. Twelve (48%) reported sexualized drug use with methamphetamine. Conclusions Eight weeks of LDV/SOF cured all 25 HIV-infected men with early HCV infection, including those who were actively using drugs. Based on these results, we recommend treatment of newly HCV-infected men during early infection, regardless of drug use, to both take advantage of this 8-week treatment and to decrease further HCV transmission among this group of men.

To the Editors:Antiretroviral agents as preexposure prophylaxis (PrEP) against HIV-1 infection are a recent and welcome addition to the prevention toolbox. Clinical trials have shown tenofovir disoproxil fumarate/emtrcitabine (TDF/FTC) as PrEP to be safe and associated with substantial reductions (4

PURPOSE OF REVIEW Clinically relevant monoclonal antibodies (mAb) to host cellular receptors have been generated to both the CD4 receptor and the CCR5 coreceptor, cell surface proteins critical for HIV-1 entry. Ibalizumab is a novel humanized mAb that binds to a conformational epitope on CD4 and blocks entry of HIV-1. It has broad and potent antiviral activity in vitro and in vivo. PRO 140 is a humanized mAb that binds to the CCR5 coreceptor and inhibits CCR5-tropic HIV-1 by interfering with viral entry. Antiviral activity has been demonstrated both in vitro against R5 viruses and in vivo in HIV-1-infected individuals harboring CCR5-tropic virus. RECENT FINDINGS Both antibodies have been administered intravenously in early-phase clinical trials, and current emphasis is on the development of formulations that can be administered subcutaneously. Most recently, bispecific antibodies combining either ibalizumab or PRO 140 with anti-Env broadly neutralizing antibodies have been constructed with vastly improved in-vitro neutralizing profiles, and may offer substantial advantages in the clinic. SUMMARY mAb to host cellular receptors particularly when combined with broadly neutralizing antibodies in novel conformations may offer advances in both the treatment and prevention of HIV-1 infection.

HIV is a member of the lentivirus subfamily of retroviruses. Two distinct groups of viruses are pathogenic in humans: HIV-1 and HIV-2. Both are transmitted sexually and known to cause immunodeficiency disease. HIV enters the cell through use of the CD4 receptor and chemokine co-receptors, primarily CCR5 and CXCR4. The viral genome is transcribed from RNA to DNA by reverse transcriptase and integrated into the host genome by integrase. The HIV genome encodes 15 proteins, comprising three categories: structural, regulatory, and accessory. After budding from the host cell, the virus matures into its infectious form through cleavage of viral precursor proteins by protease.

Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P < 0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R = −0.85, P = 0.004) and positively with baseline plasma viral load (Spearman's R = 0.81, P = 0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A*31 and B*37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8 + T-cell pressures play a role in this phenomenon. IMPORTANCE Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.

High levels of immune activation are reported for people who inject drugs. Studies of the relationship between injection behaviors and immune activation have yielded mixed results, in part due to lack of control for hepatitis C virus in analyses. This study, of 48 HIV-seronegative people who inject drugs, examines this relationship controlling for hepatitis C virus viremia. Frequency of injection was positively related to markers of immune activation (soluble CD14, %CD8CD38HLADR T cells), as was duration of injection (high-specificity C-reactive protein and D-dimer). Sharing injection equipment was not related to markers studied. Findings suggest that efforts to encourage injection cessation or reduction in frequency can have positive health benefits through reducing immune activation.

Objective We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection. Design CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques. Methods Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. Results CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection. Conclusion These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.

(See the Editorial Commentary by Zeremski et al on pages 880–2.) Hepatitis C virus (HCV) chronically infects an estimated 5.2 million people in the United States and 170 million people worldwide [1]. However, as most initial (“acute”) infections are completely asymptomatic, newly infected people are rarely identified. The importance of finding these newly HCV-infected people during the acute phase was made clear in the seminal paper by Jaeckel et al [2] that showed a nearly 100% sustained virologic response (SVR) rate using just 24 weeks of interferon alone, an SVR rate many times higher than that of chronically infected patients at that time, and with just half the duration of interferon [3]. We are now faced with an entirely new group of patients who are becoming HCV infected in the international epidemic of sexually transmitted HCV infection among human immunodeficiency virus (HIV)–infected men who have sex with men (MSM). Published cure rates after treatment of acute HCV in these men, using pegylated interferon (peg-IFN) plus ribavirin (RBV) for 24–48 weeks’ duration, are not as good as those of Jaeckel et al [2], ranging from 53% to 83% [4–15], but are clearly better than the 27%–40% success rates in treatment of chronic HCV in HIV-infected men [16, 17]. Still, even with 48 weeks of treatment in many of these studies of acute HCV, fewer than two-thirds of patients achieved SVR, leaving a large proportion of these men uncured, with the possibility of experiencing rapidly advancing liver disease [18–21] and of infecting others and further propagating the epidemic. With the commercial availability of telaprevir (TVR) in the United States, we hypothesized that its potent activity against genotype 1 HCV would allow us to further shorten the treatment period while also improving the SVR rate. We therefore undertook a study of a 12-week treatment course with a combination of TVR, peg-IFN, and RBV in HIV-infected MSM with newly acquired genotype 1 HCV.

The integrase enzyme facilitates the incorporation of HIV-1 proviral DNA into the host cell genome and catalyses a function vital to viral replication. Inhibitors of this enzyme represent the newest class of antiretroviral drugs in our armamentarium to treat HIV-1 infection. Raltegravir, an integrase strand transfer inhibitor, was the first drug of this class approved by the US FDA; it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance. These qualities have prompted the search for agents with once-daily dosing, a more robust barrier to resistance, and a resistance profile of limited overlap with that of raltegravir. We review a series of integrase inhibitors that are in clinical or advanced pre-clinical studies. Elvitegravir, recently approved by the FDA as part of the elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir. Dolutegravir is the most advanced second-generation integrase inhibitor, and it boasts good tolerability, once-daily dosing with no need for a pharmacological enhancer, and relatively little cross-resistance with raltegravir. S/GSK1265744 has been developed into a long-acting parenteral agent that shows a high barrier to resistance in vitro and the potential for an infrequent dosing schedule. BI 224436 is in early clinical trials, but is unlikely to demonstrate cross-resistance with other integrase inhibitors. The inhibitors of the lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase (LEDGINs) are extremely early in development. Each of these contributes a new benefit to the class and will extend the treatment options for patients with HIV-1 infection.

Background. Chronic inflammation, as defined by persistent immune activation, is associated with adverse clinical outcomes. People who inject drugs (PWID) have evidence of persistent immune activation. Here, in a cohort of PWID with or without hepatitis C virus (HCV) infection, we sought to dissect out the contribution of chronic HCV infection (common in PWID) from the effects of injection drug use itself. Methods. Four groups of study volunteers were recruited: group 1 comprised active PWID; group 2, individuals who ceased injecting drugs 1–2 months before recruitment; group 3, individuals who ceased injecting drugs 3–4 months before recruitment; and group 4, healthy volunteers. Soluble and cell-associated markers of immune activation were quantified. Results. HCV-viremic PWID have elevated levels of immune activation when compared to healthy volunteers. Cessation of injection drug use results in a decline in immune activation in the absence of HCV viremia, while HCV-viremic individuals who previously were PWID continue to harbor elevated levels of immune activation, as defined by increased levels of soluble CD14 and tumor necrosis factor α and by the presence of CD38+HLA-DR+ CD4+ and CD8+ T cells. Conclusions. Immune activation, a well-defined surrogate of poor clinical outcome that is elevated in PWID, can regress to normal levels in former injection drug users who are HCV aviremic. Therefore, enhanced harm-reduction efforts should incorporate aggressive treatment of HCV infection. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01831284","term_id":"NCT01831284"}}NCT01831284.

Recruitment of people who use drugs (PWUD) for HIV-related research has been undertaken since early in the epidemic. In early studies, recruitment was often performed by outreach workers with familiarity with the target population, who distributed risk reduction materials, and administered the surveys being conducted on drug use and risk behaviors. The evolution of effective treatments for HIV has provided opportunities for PWUD to participate in biobehavioral studies testing the efficacy of medical treatment advances and exploring the underlying biomedical basis for prevention and treatment efforts. Recruitment for these studies has led to new challenges for outreach workers and institutions conducting this research. PWUD, particularly those from race/ethnic minority populations, have had lower rates of engagement in HIV care and have been underrepresented in HIV/AIDS medical studies. To address these health disparities, enhanced efforts are needed to increase their participation in biomedical studies. This article examines the challenges identified by experienced outreach workers in recruiting PWUD for HIV-related biomedical studies, including individual (participant)-, institutional-, and recruiter-level challenges, and provides recommendations for addressing them.

Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV in-fection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.

Objective: Injection drug use (IDU) remains a major risk factor for HIV-1 acquisition. The complex interplay between drug use, non-sterile injection, and Hepatitis C remains poorly understood. We conducted a pilot study to determine the effect of IDU on immune parameters among HIV-uninfected and -infected individuals. We hypothesized that IDU could further augment immunological changes associated with HIV-1 infection, which could in turn affect HIV pathogenesis Methods: HIV-uninfected and -infected subjects with IDU, and non-IDU controls were recruited to obtain socio-demographic and drug-related behaviours. Blood (PBMC) and mucosal (MMC) mononuclear cells were analysed for cellular markers of immune activation (CD38 and Ki67). Serum ELISA was performed to determine levels of soluble CD14, a marker of immune activation. Results: No significant quantitative differences in CD4+ and CD8+ T cell levels were observed between IDU and non-IDU subjects when accounting for the presence of HIV-1 infection. However, increased levels of cellular and soluble markers of immune activation were documented in cells and plasma of HIV-uninfected IDU subjects compared to non-injectors. Additionally, sharing of injection paraphernalia was related to immune activation among HIV-uninfected IDU subjects. Conclusion: IDU, with or without HIV-1 infection, results in a significant increase in immune activation in both the peripheral blood and the GI tract. This may have significant impact on HIV transmission, pathogenesis, and immunologic responses to combination antiviral therapy. This study provides compelling preliminary results which in turn support larger studies to better define the relationship between IDU, infection with HIV-1, co-infection with Hepatitis C and immunity.

Human leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era. IMPORTANCE HLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may accumulate in circulation over time, potentially undermining host antiviral immunity to the transmitted viral strain. We studied >600 experimentally collected HIV-1 polymerase sequences linked to host HLA information dating back to 1979, along with phylogenetically reconstructed HIV-1 sequences dating back to the virus' introduction into North America. Overall, our results support the gradual spread of many—though not all—HIV-1 polymerase immune escape mutations in circulation over time. This is consistent with recent observations from other global regions, though the extent of polymorphism accumulation in North America appears to be lower than in populations with high seroprevalence, older epidemics, and/or limited HLA diversity. Importantly, the risk of acquiring an HIV-1 polymerase sequence at transmission that is substantially preadapted to one's HLA profile remains relatively low in North America, even in the present era.

Raltegravir as initial HIV therapy was examined in a double-blind study; 160 patients were randomized to raltegravir (400 mg bid after dose-ranging), 38 to efavirenz, both with tenofovir/lamivudine. At week 240, HIV-RNA remained

An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naïve individuals with early ( n = 88) and chronic ( n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection ( R = −0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and -B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF 114–121 ) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ∼35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA-driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies.

Objective: To determine the prevalence of HIV-associated neurocognitive disorders (HAND) in HIV-infected participants who initiated combination antiretroviral therapy (cART) during primary infection. Design: Cross-sectional observational study. Methods: HIV-infected men without neuropsychiatric confounds who had initiated cART during primary infection were administered a neuropsychological battery as well as questionnaires evaluating depression and quality of life. Eligibility was determined by a medical examination with history and review of records. Results: Twenty-six primarily non-Hispanic white (73%), male (100%) participants were enrolled and underwent neurocognitive assessment. Mean age was 43 (28–71) years, with a median of 17 years of education (13–24). Median current and nadir CD4 þ T-cell counts were 828 (506–1411) and 359 (150–621) cells/ml. All participants had plasma HIV-1 RNA less than 50 copies/ml. Median duration of cART prior to enrolment was 5.7 years (2.2–9.9). Median global deficit score was 0.17 (0.00–0.60). Only one (4%) participant was impaired. Conclusion: Rates of HAND in this cohort of HIV-infected men without comorbid conditions who initiated early cART are low. Our findings suggest a possible neuroprotective benefit of early cART and an important contribution of comorbidities to observed HAND prevalence.

Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigens, The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after somatic mutations. Polyreactive gp41-binding antibodies were also isolated from uninfected individuals. These data suggest that the majority of gp41-binding antibodies produced after acute HIV-1 infection are cross-reactive responses generated by stimulating memory B cells that have previously been activated by non–HIV-1 antigens.

Background. Identifying persons with recent human immunodeficiency virus (HIV) antibody seroconversion is useful for treatment, research, and prevention, but the sensitivity and specificity of tests for this purpose are uncertain. Methods. We used longitudinal specimens panels from 155 persons identified prior to HIV seroconversion to assess antibody-based methods for classifying persons as within 30, 60, or 90 days of seroconversion, including 2 incidence assays, a less-sensitive (LS) enzyme immunoassay (EIA), and the BED assay. Results. Sensitivity and specificity, respectively, for identifying persons within 30 days of seroconversion were: 34%–57% and 98%–100% for 2 standard EIAs (employing a signal-to-cutoff ≤4.0; ≥1.0 defines HIV positive), 84% and 73% for the LS-EIA (≤0.2 cutoff), 88% and 72% for the BED (≤0.2 cutoff), and 43%–58% and 98% (≤3 bands) for 2 Western blot (WB) assays. By area under the receiver operator curves, the best test for identifying persons within 30 days of seroconversion was the number of bands on the Bio-Rad WB (0.90); within 60 days, the LS-EIA and BED (both 0.85); and for persons within 90 days the BED (0.86). Conclusions. Standard EIAs, Western blots, and HIV incidence assays provide useful information for identifying persons 30 to 90 days after seroconversion.

Integrase inhibitors are the newest class of antiretroviral agents developed to treat HIV-1 infection. Raltegravir (RAL), the only integrase inhibitor (INI) currently approved for the treatment of HIV-infected patients, has proven to be a potent and well-tolerated antiretroviral (ARV) agent. It is currently approved and used for the treatment of both ARV-experienced and ARV-naive patients. Nevertheless, the relatively low genetic barrier for resistance of RAL encourages the search for new INIs with different mechanisms of actions and resistance profiles.Here we review the data available about INI that are currently being tested in clinical trials or are in preclinical development: elvitegravir (EVG), S/GSK1349572, S/GSK1265744 and LEDGINs. We focus on their clinical efficacy, pharmacokinetic, safety and resistance profiles.Up-to-date overview on the currently available, clinically relevant INIs and promising preclinical inhibitors at all phases of development.Integrase inhibitors represent the newest therapeutic class available to treat HIV-1 infection. There are a variety of compounds either available in the clinic (RAL), advancing to Phase III trials (EVG), or in earlier phases of development. Taken together, this class offers new treatment options for the HIV-infected individual.

The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection.Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNAor =5000 copies per milliliter and CD4 T cellsor =100 cells per microliter.One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients (1 in each group) met the protocol definition of virologic failure between weeks 48 and 96; no known resistance mutations were observed in the raltegravir recipient; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations. Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. Raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir.In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. Raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.

Methicillin-resistant Staphylococcus aureus (MRSA) carriage and subsequent infection were prospectively compared among a well-defined group of 107 individuals infected with human immunodeficiency virus type 1 (HIV-1) who had no evidence of immune suppression and 52 epidemiologically matched, uninfected individuals. The carriage strains and infecting strains were genetically characterized. The cumulative prevalence of MRSA carriage was significantly higher among HIV-infected individuals (16.8%) than among individuals without HIV infection (5.8%) (P = .04; odds ratio, 3.3 [95% confidence interval, 1.3-14.7]). Fifteen of 21 MRSA isolates recovered from colonized individuals were identified as strain USA300. Of the 10 MRSA skin and soft tissue infections observed in this study, all occurred in HIV-infected individuals who were colonized with the same strain that caused the infection. Previous antibiotic use was the only statistically significant risk factor for MRSA carriage. These data highlight the fact that MRSA colonization and infection are important clinical issues among asymptomatic HIV-1-infected individuals.