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HIV infections are ongoing globally despite efficacious biomedical prevention options. We sought to determine whether an HIV prevention package providing choice of daily pills or long-acting injectable cabotegravir and opportunities to change prevention options could increase biomedical prevention coverage and reduce new HIV infections.

San Francisco implemented one of the most intensive, comprehensive, multipronged COVID-19 pandemic responses in the United States using 4 core strategies: (1) aggressive mitigation measures to protect populations at risk for severe disease, (2) prioritization of resources in neighborhoods highly affected by COVID-19, (3) timely and adaptive data-driven policy making, and (4) leveraging of partnerships and public trust. We collected data to describe programmatic and population-level outcomes. The excess all-cause mortality rate in 2020 in San Francisco was half that seen in 2019 in California as a whole (8% vs 16%). In almost all age and race and ethnicity groups, excess mortality from COVID-19 was lower in San Francisco than in California overall, with markedly diminished excess mortality among people aged >65 years. The COVID-19 response in San Francisco highlights crucial lessons, particularly the importance of community responsiveness, joint planning, and collective action, to inform future pandemic response and advance health equity.

Social and cognitive developmental events can disrupt care and medication adherence among adolescents and young adults living with HIV in sub-Saharan Africa. We hypothesised that a dynamic multilevel health system intervention helping adolescents and young adults and their providers navigate life-stage related events would increase virological suppression compared with standard care.

Despite longstanding guidelines endorsing isoniazid preventive therapy (IPT) for people with HIV, uptake is low across sub-Saharan Africa. Mid-level health managers oversee IPT programmes nationally; interventions aimed at this group have not been tested. We aimed to establish whether providing structured leadership and management training and facilitating subregional collaboration and routine data feedback to mid-level managers could increase IPT initiation among people with HIV compared with standard practice.

Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective.

The ability to quantitate human immunodeficiency virus (HIV) in blood and tissues from patients at all stages of disease has provided new insights into the pathogenesis of HIV disease. There is a dynamic equilibrium between HIV production and clearance even during the period of clinical latency, which;. may permit resistant virus to emerge with the imposition of drug pressure. Disruption of the equilibrium with effective drugs reduces circulating levels of HIV within 1 week, thus allowing the rapid assessment of new candidate drugs. To maximize the magnitude and durability of HIV RNA suppression, therapeutic strategies must be implemented that are effective against high levels of rapidly replicating virus that consist of many genetic variants., Tests that evaluate levels of human immunodeficiency virus (HIV) ribonucleic acid (RNA) appear to be useful in monitoring disease progression and drug effectiveness in patients with HIV. HIV RNA is the viral genetic material. The virus reproduces as quickly as every six hours, allowing for increased opportunities for mutations or changes in its genetic makeup. Studies have shown that HIV RNA levels accurately reflect and predict disease progression even in the early stages of the disease. HIV RNA tests can also provide quick feedback on patients' virus levels in response to drug treatment. Early and ongoing combination drug therapies that target possible viral mutations as well as viral reproductive capability appear to hold the most promise for effective management of this disease.

Nevirapine appears to be well tolerated and have some beneficial effect in HIV-infected patients. Nevirapine is an antiviral drug that inhibits enzymes involved in the reproduction of HIV. Researchers conducted a clinical trial of nevirapine alone and in combination with zidovudine, another antiviral drug, among 62 HIV-infected patients. Patients received doses of 12.5, 50 and 200 milligrams (mg) of nevirapine alone or in combination with 200 mg doses of zidovudine every eight hours. By day 7 of the trial, blood levels of HIV infection markers fell to a minimum level in the majority of patients. Blood levels of HIV genetic material decreased by at least 50% after four weeks of treatment in four of ten patients receiving either 50 mg or 200 mg of nevirapine. Most patients experienced fatigue or extreme sleepiness as a side effect of the drug. Other side effects included headache, diarrhea, nausea, fever and rash.

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Optimal strategies for pre-exposure prophylaxis (PrEP) engagement in generalised HIV epidemics are unknown. We aimed to assess PrEP uptake and engagement after population-level HIV testing and universal PrEP access to characterise gaps in the PrEP cascade in rural Kenya and Uganda.

The integrase inhibitor dolutegravir is being considered in several countries in sub-Saharan Africa instead of efavirenz for people initiating antiretroviral therapy (ART) because of superior tolerability and a lower risk of resistance emergence. WHO requested updated modelling results for its 2019 Antiretroviral Guidelines update, which was restricted to the choice of dolutegravir or efavirenz in new ART initiators. In response to this request, we modelled the risks and benefits of alternative policies for initial first-line ART regimens.

There is concern over increasing prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance in people initiating antiretroviral therapy (ART) in low-income and middle-income countries. We assessed the effectiveness and cost-effectiveness of alternative public health responses in countries in sub-Saharan Africa where the prevalence of pretreatment drug resistance to NNRTIs is high.

Rifabutin therapy for the prevention of Mycobacterium (M.) avium complex infection in HIV-positive persons may cause uveitis. Uveitis is an inflammation of the iris of the eye, characterized by eye pain and loss of visual acuity. M. avium complex infection is a serious bacterial disease to which immunocompromised HIV patients are susceptible. Four HIV-infected homosexual males developed uveitis in one eye after seven to 14 months of rifabutin therapy. They were all treated with topical prednisolone and atropine, and three continued rifabutin therapy. Two of the patients continuing rifabutin subsequently developed uveitis in the other eye and stopped taking rifabutin. They had no further recurrences of uveitis. Other studies have also reported the association of uveitis with rifabutin therapy.

Intermittent treatment with sulfadoxine–pyrimethamine, recommended for prevention of malaria in pregnant women throughout sub-Saharan Africa, is threatened by parasite resistance. We assessed the efficacy and safety of intermittent preventive treatment with dihydroartemisinin–piperaquine as an alternative to sulfadoxine–pyrimethamine.

Viral suppression among HIV-positive individuals is essential for protecting health and preventing HIV transmission. Financial incentives have shown promise in modifying various health behaviours in low-income countries but few studies have assessed whether they can improve HIV treatment outcomes. We aimed to determine the impact of time-limited financial incentives on viral suppression among HIV-positive adults in rural Uganda.

The integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains.

Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate is highly protective against HIV infection. We report a case of tenofovir-susceptible, emtricitabine-resistant HIV acquisition despite high adherence to daily PrEP.

Background: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. Objective: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. Design: Open-label extension of a randomized, double-blind study. Setting: Four clinical research units. Patients: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20 000 copies/mL and CD4 counts ranging from 50 to 400 cells/[mm.sup.3]. Intervention: Indinavir, zidovudine, and lamivudine. Measurements: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. Results: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/[mm.sup.3] (interquartile range, 150 to 316 cells/[mm.sup.3]). Nephrolithiasis occurred in 12 of 33 patients (36%). Conclusion: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.

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In HIV disease, the pendulum has recently swung toward delaying initiation of antiretroviral therapy. I would like to highlight potential pitfalls of this new approach and, perhaps, push the pendulum [...]

Reducing tuberculosis (TB) deaths among children requires a better understanding of the gaps in the care cascade from TB diagnosis to treatment completion. We sought to assess the child TB care cascade in 32 rural communities in Uganda and Kenya using programmatic data.

As sub-Saharan Africa transitions to a new era of universal antiretroviral therapy (ART), up-to-date assessments of population-level HIV RNA suppression are needed to inform interventions to optimise ART delivery. We sought to measure population viral load metrics to assess viral suppression and characterise demographic groups and geographical locations with high-level detectable viraemia in east Africa.

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In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.

The persistence of latent HIV proviruses in long-lived CD4+T cells despite antiretroviral therapy (ART) is a major obstacle to viral eradication. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4+T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.

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Despite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population-wide testing coverage.

Efficient ways to identify children with HIV in the context of universal test-and-treat policies are needed. We evaluated a hybrid testing strategy combining mobile community and home-based HIV testing in 87,700 children across 32 rural communities in 2 East African countries. This approach resulted in 81% testing coverage of at-risk children and doubled the number of children diagnosed with HIV.

ABSTRACTChanging treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivodrug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparumsamples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivodrug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt76T, as well as increased lumefantrine sensitivity with pfmdr186Y, Y184, and 1246Y. Over time, ex vivosensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrtK76 and pfmdr1N86 and D1246 increased, and the prevalences of pfdhfrand pfdhpspolymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivolumefantrine sensitivity and increased prevalence of pfcrtK76 and pfmdr1N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr186Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.