Treatment of chronic hepatitis B virus (HBV) infections with the reverse transcriptase inhibitor lamivudine leads to a rapid decline in plasma viremia and provides estimates for crucial kinetic constants of HBV replication. We

BACKGROUNDTwo drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeiciency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low-and middle-income countries. METHODSWe conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs -TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) -against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTSA total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONSTreatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.

investments to support countries with greatest burden of viral hepatitis All heavily burdened countries to have fully funded elimination plans by 2019 Recognition of need to focus on high burden countries and support for national policy development (All) Funding for national elimination plans Creation of fiscal space for new programmes with costed investment programmes Adopt domestic innovative finance tools where appropriate Support national policy makers in their activity (WHO, UNITAID, NGOs) Provide international support for financing measures (UNITAID, GFATM, bilaterial donors) Prevention Ensure all WHO elimination targets addressed in plans Address operational challenges in delivery of birth dose HBV vaccine Ensure provision of harm reduction services and engage with marginalised group (e.g. prisoners, PWIDs). Ensure clear public health messages to encourage testing and treatment Support countries to decriminalise injecting drug use and ensure equitable access to services for all (NGOs, WHO, civil society) Ensure appropriate funding for HBV vaccine, including birth dose (GAVI, WHO) Support R&D into HCV vaccine development (Research funders and pharma) Testing and Models of Care Focus on substantially scaling up testing for HBV and HCV Create and evaluate simplified care pathways relevant to local setting, integrating with existing services. Promote task sharing and decentralisation of care through capacity building, training and removal of Support operational research into simplified pathways (Research funders, UNITAID) requirements for specialised prescribing Diagnostics Ensure testing is integrated into the wider healthcare system, rather than centralised facilties Ensure access to quality diagnostics through Essential Diagnostic List and prequalification (WHO, funders) Support implementation science for models of care and R&D into novel diagnostics suitable for decentralised settings. (Research funders, FIND, industry) Access to treatment Ensure all Essential Medicines for viral hepatitis are included in national programmes, with an emphasis on pan-genotypic regimens Apply comprehensive policy approach to promoting access, including compulsory licensing Ensure all essential medicines are pre-qualified and either available through voluntary licensing or Medicines Patent Pool (WHO, NGOs, civil society, funders) Support shared procurement mechanisms for treatment (PAHO) Monitor Progress National plans need clearly defined, measurable objectives Develop new indices of national progress Progress of individual countries needs to be closely monitored towards elimination goals (Polaris, WHO, Creation of Elimination Index) Develop greater capacity for advocacy in high burden regions (all) Viral hepatitis is one of the leading causes of death in the world. 96% of those deaths are due to hepatitis B and C, which are the focus of this commission. Unlike many other major diseases, the tools exist to eliminate viral hepatitis. A highly effective vaccine is available to prevent hepatitis B, and a revolution in HCV treat...

SummaryBackgroundThe emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings.MethodsWe did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models.FindingsStudy-level data were available for 26 102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (–0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region.InterpretationOur findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries—no changes in antiretroviral treatment guidelines are warranted at the moment.FundingBill & Melinda Gates Foundation and the European Community's Seventh Framework Programme

Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.