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Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference −3·7%, 95% CI −6·1 to −1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. ViiV Healthcare.

This randomized, open-label trial compared two regimens for the initial treatment of human immunodeficiency virus (HIV) infection: tenofovir disoproxil fumarate and emtricitabine plus efavirenz or a fixed dose of zidovudine and lamivudine plus efavirenz. Through week 48, the first regimen was superior in terms of viral suppression, CD4-cell response, and adverse events leading to discontinuation of the medication. As this trial continues, it will be important to assess any differences in long-term toxic effects, especially with regard to lipoatrophy and hyperlipidemia. For the initial treatment of HIV, a regimen of tenofovir and emtricitabine plus efavirenz was superior in terms of viral suppression, CD4-cell response, and adverse events through week 48. Highly active antiretroviral therapy has fundamentally altered the course of human immunodeficiency virus (HIV) infection by making it possible to suppress the plasma viral load below the limit of detection and to increase the number of CD4 cells. 1 The cornerstone of durable suppression of HIV replication is maintenance of a potent and tolerable regimen to which the patient can adhere. Adherence is necessary to prevent the emergence and replication of drug-resistant strains of the virus. 2 Current guidelines for the management of HIV infection recommend the use of zidovudine or tenofovir disoproxil fumarate (DF) with lamivudine or emtricitabine as preferred nucleoside . . .

Background. Coinfection with human immunodeficiency virus type 1 (HIV-1) increases the risk of hepatitis B virus (HBV)-associated progressive liver disease. Lamivudine has potent activity against both HIV-1 and HBV; however, lamivudine-resistance mutations in HBV frequently develop. Methods. Substudies of the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF) for patients coinfected with HIV and HBV were undertaken within 2 phase 3 randomized controlled trials involving antiretroviral therapy-experienced (study 907) and -naive (study 903) HIV-infected populations. Inclusion criteria were detection of hepatitis B surface antigen, an HBV DNA level >106 copies/mL at baseline, and HBV DNA specimens available at week 24 (study 907) and week 48 (study 903). Results. In study 907, the mean decrease in HBV DNA was 4.9 log10, after 24 weeks, for 10 patients randomized to receive tenofovir DF, compared with a mean increase of 1.2 log10 for 2 patients randomized to receive placebo (P=.041). The mean decrease in HBV DNA during tenofovir DF treatment was similar for patients with wildtype (5.3 log10) and lamivudine-resistant (4.6 log10) HBV strains. In study 903, the mean decrease in HBV DNA was 3.0 log10, after 48 weeks, for 6 patients randomized to receive lamivudine, compared with 4.7 log10 for 5 patients randomized to receive lamivudine and tenofovir DF (P=.055). Four patients developed tyrosine-methionine- aspartate-aspartate mutations, all in the lamivudine-only treatment arm. Conclusion. Tenofovir DF has potent anti-HBV efficacy in antiretroviral therapy-experienced and -naive individuals coinfected with HIV and HBV.

Background People living with human immunodeficiency virus (PLHIV) have a similar prevalence of psoriasis as the general population, though incidence and severity correlate with HIV viral load. Adequately treating HIV early renders the infection a chronic medical condition and allows PLHIV with a suppressed viral load (PLHIV-s) to live normal lives. Despite this, safety concerns and a lack of high-level data have hindered the use of systemic psoriasis therapies in PLHIV-s. Objectives We aim to provide a structured framework that supports healthcare professionals and patients discussing the risks and benefits of systemic psoriasis therapy in PLHIV-s. Our goal was to address the primary question, are responses to systemic therapies for the treatment of psoriasis in PLHIV-s similar to those in the non-HIV population? Methods We implemented an inference-based approach relying on indirect evidence when direct clinical trial data were absent. In this instance, we reviewed indirect evidence supporting inferences on the status of immune function in PLHIV. Recommendations on systemic treatment for psoriasis in PLHIV were derived using an inferential heuristic. Results We identified seven indirect indicators of immune function informed by largely independent bodies of evidence: (1) functional assays, (2) vaccine response, (3) life expectancy, (4) psoriasis manifestations, (5) rate of infections, (6) rate of malignancies, and (7) organ transplant outcomes. Conclusions Drug-related benefits and risks when treating a patient with systemic psoriasis therapies are similar for non-HIV patients and PLHIV with a suppressed viral load and normalized CD4 counts. Prior to initiating psoriasis treatment in PLHIV, HIV replication should be addressed by an HIV specialist. Exercise additional caution for patients with a suppressed viral load and discordant CD4 responses on antiretroviral therapy. Plain Language Summary People living with human immunodeficiency virus (PLHIV) develop psoriasis as often as everyone else. We asked: what are effective and safe treatments when PLHIV need systemic therapy (pills or injections) for their psoriasis? HIV infection attacks the immune system. When HIV is not treated, the immune system declines. A less effective immune system makes it harder for the body to fight infections and certain cancers. Psoriasis is a skin condition caused by overactive immune cells. Effective psoriasis treatments reduce immune-cell activity. There are some concerns that treatments for psoriasis may not work and could worsen infections or cancers. To answer the question, we gathered 11 dermatologists and 4 HIV specialists. We reviewed the international scientific literature on PLHIV and psoriasis. The absence of direct evidence and volume of information to review made the process challenging. The end results were worthwhile. We concluded that people who are diagnosed early and take antiretroviral therapy to control their HIV infection (PLHIV-c) can live long, healthy lives. Accordingly, we determined that PLHIV-c can likely expect the same safety and efficacy for systemic psoriasis treatments as the general population. Treatment decisions should be made on a case-by-case basis through consultation with the patient and treating physician(s). Pillars of modern medicine are evidence-based care and collaborative decision-making. Too often, neither care provider nor patient are adequately informed. We have tried to fill one information gap for PLHIV and psoriasis. This process may help answer questions in other disease populations where direct evidence is scarce or absent.

Introduction There have been several important developments in antiretroviral treatment in the past two years. Randomized clinical trials have been conducted to evaluate a lower dose of efavirenz (400 mg once daily). Integrase inhibitors such as dolutegravir have been approved for first‐line treatment. A new formulation of tenofovir (alafenamide) has been developed and has shown equivalent efficacy to tenofovir in randomized trials. Two‐drug combination treatments have been evaluated in treatment‐naïve and ‐experienced patients. The novel pharmacokinetic booster cobicistat has been compared to ritonavir in terms of pharmacokinetics, efficacy and safety. The objective of this commentary is to assess recent developments in antiretroviral drug treatment to determine whether new treatments should be included in new international guidelines. Discussion The use of first‐line treatment with tenofovir and efavirenz at the standard 600 mg once‐daily dose should remain the first‐choice standard of care treatment. Evidence supporting a switch to efavirenz 400 mg once daily or integrase inhibitors is sufficient to consider these drugs as alternative first‐line options, but more data are needed on their use in pregnant women and people with TB co‐infection. The use of new formulations of tenofovir is currently too preliminary to justify immediate adoption and scale‐up across HIV programmes in low‐ and middle‐income countries. The evidence supporting use of two‐drug combinations is not considered strong enough to justify changed recommendations from use of standard triple drug combinations. Cobicistat does not offer significant safety advantages over ritonavir as a pharmacokinetic booster. Conclusions For continued scale‐up of antiretroviral treatment in low‐ and middle‐income countries, use of first‐line triple combinations including efavirenz 600 mg once daily is supported by the largest evidence base. Additional studies are underway to evaluate new treatments in key populations, and these results may justify changes to these recommendations.

The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown. Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation). Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8⁺ T cells were indistinguishable between the two arms and did not change over time between the groups. Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.

Introduction Rifabutin, a rifamycin of equivalent potency to rifampicin, has several advantages in its pharmacokinetic and toxicity profile, particularly in HIV co‐infected patients on combined antiretroviral therapy (cART). In this commentary, we evaluate evidence supporting increased global use of rifabutin and highlight key recommendations for action. Discussion Although extrapolation of data from HIV uninfected patients would suggest non‐inferiority, there has been no randomized controlled study comparing rifabutin versus rifampicin in the outcomes of relapse‐free cure, in drug susceptible tuberculosis (TB), in HIV co‐infected patients on currently utilized cART regimens or in paediatric populations. An important advantage of rifabutin is that compared to the dose adjustments required with rifampicin, it can be co‐administered with the integrase strand transfer inhibitors raltegravir or dolutegravir without the need for dose adjustments. This strategy would be easier to implement in a programmatic setting and would save costs. We have assessed cost incentives to utilize rifabutin and have estimated generic costs for a range of rifabutin dosage scenarios. Where facilities are present for drug re‐challenge and monitoring for drug toxicity and cross‐reactivity, rifabutin offers a switch alternative for adverse drug reactions (ADR)s attributed to rifampicin. This would negate the need to prolong treatment in the absence of a rifamycin as part of short‐course multidrug therapy. There is evidence of incomplete cross‐resistance to rifampicin and rifabutin. Rifabutin may be useful in rifampicin‐resistant TB, in an estimated 20% of cases, based on phenotypic or genotypic rifabutin susceptibility testing. Conclusions Rifabutin should be available globally as a first‐line rifamycin in HIV co‐infected individuals and as a switch option in cases of rifampicin associated ADRs. Further studies are needed to ascertain the utility of rifabutin in rifampicin‐resistant rifabutin‐susceptible TB.

Latent TB infection (LTBI) screening and treatment in HIV-positive individuals in the UK is advocated by the British HIV Association (BHIVA) and National Institute for Health and Care Excellence (NICE), although each recommends differing strategies. We undertook an evaluation of UK practice, relating the responses to the local HIV/TB disease burden. 162 of 188 (86%) UK geographical areas responded; only 93/162 (57.4%) offer LTBI testing with considerable heterogeneity in practice, and no difference in HIV/TB burden between areas offering testing and those who do not. Only 33/93 (35.5%) and 6/93 (6.5%) reported full compliance with BHIVA and NICE guidance respectively. A uniform national guideline is required.