Summary Background Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate ...antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. Methods The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT00074581. Findings 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373–522) cells per μL in patients assigned to the early treatment group and 428 (357–522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197–249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52–1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43–0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28–0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5–27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5–32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. Interpretation Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. Funding US National Institute of Allergy and Infectious Diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background HIV transmission risk is higher during acute and early HIV infection than it is during chronic infection, but the contribution of early infection to the spread of HIV is ...controversial. We estimated the contribution of early infection to HIV incidence in Lilongwe, Malawi, and predict the future effect of hypothetical prevention interventions targeted at early infection only, chronic infection only, or both stages. Methods We developed a deterministic mathematical model describing heterosexual HIV transmission, informed by detailed behavioural and viral-load data collected in Lilongwe. We included sexual contact within and outside of steady pairs and divided the infectious period into intervals to allow for changes in transmissibility by infection stage. We used a Bayesian melding approach to fit the model to HIV prevalence data collected between 1987 and 2005 at Lilongwe antenatal clinics. We assessed interventions that reduced the per-contact transmission probability to 0·00003 in people receiving them, and varied the proportion of individuals receiving the intervention in each stage. Findings We estimated that 38·4% (95% credible interval 18·6–52·3) of HIV transmissions in Lilongwe are attributable to sexual contact with individuals with early infection. Interventions targeted at only early infection substantially reduced HIV prevalence, but did not lead to elimination, even with 100% coverage. Interventions targeted at only chronic infections also reduced HIV prevalence, but coverage levels of 95–99% were needed for the elimination of HIV. In scenarios with less than 95% coverage of interventions targeted at chronic infections, additional interventions reaching 25–75% of individuals with early infection reduced HIV prevalence substantially. Interpretation Our results suggest that early infection plays an important part in HIV transmission in this sub-Saharan African setting. Without near-complete coverage, interventions during chronic infection will probably have incomplete effectiveness unless complemented by strategies targeting individuals with early HIV infection. Funding National Institutes of Health, University of North Carolina Center for AIDS Research.
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We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the ...population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Community viral load, defined as an aggregation of individual viral loads of people infected with HIV in a specific community, has been proposed as a useful measure to monitor HIV treatment ...uptake and quantify its effect on transmission. The first reports of community viral load were published in 2009, and the measure was subsequently incorporated into the US National HIV/AIDS Strategy. Although intuitively an appealing strategy, measurement of community viral load has several theoretical limitations and biases that need further assessment, which can be grouped into four categories: issues of selection and measurement, the importance of HIV prevalence in determining the potential for ongoing HIV transmission, interpretation of community viral load and its effect on ongoing HIV transmission in a community, and the ecological fallacy (ie, ecological bias). These issues need careful assessment as community viral load is being considered as a public health measurement to assess the effect of HIV care on prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Syphilis is a persistent public health issue in many low-income countries that have limited capacity for testing, which traditionally relies on a sensitive non-treponemal test and then a ...specific treponemal test. However, the development of a new rapid treponemal test provides an opportunity to scale up syphilis screening in many settings where traditional tests are unavailable. This systematic review of immunochromatographic strip (ICS) syphilis tests describes the sensitivity and specificity in two important clinical settings: sexually transmitted infection (STI) clinics and antenatal clinics. Clinical data from more than 22 000 whole blood, plasma, or fingerstick ICS tests obtained at STI or antenatal clinics were retrieved from 15 studies. ICS syphilis tests have a high sensitivity (median 0·86, interquartile range 0·75–0·94) and a higher specificity (0·99, 0·98–0·99), both comparable with non-treponemal screening test characteristics. Further research evaluating ICS syphilis tests among primary syphilis cases and among patients infected with HIV will be essential for the effective roll-out of syphilis screening programmes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Sustained viral suppression through antiretroviral therapy (ART) reduces the risk of sexual HIV transmission. However, it can require routine access to reliable and effective ...medical care, which can be difficult to obtain in resource-constrained areas. We investigated the effects of patient load and travel distance to an HIV care clinic on transmission risk in HIV serodiscordant couples in the Henan Province, China. Methods The study cohort arises from a population of HIV-infected individuals in central rural China where regional blood selling scandals in the 1990s led to mass HIV transmission of up to 30 000 people though unsanitary blood collection practices. Local disease control centres in our study prefecture followed up patients with HIV and their uninfected spouses to monitor transmission events since 2006. Eligible couples had to be registered residents living in the study prefecture, older than 16 years (the age of legal consent in China), in a stable marriage (no separation or divorce), one partner confirmed to be HIV seropositive and the other seronegative, and be willing to provide written or verbal informed consent. Cox proportional hazard models were used to compare events of HIV transmission between couples living near (<50 km), medium (≥50 km), or far (>100 km) distances from their assigned HIV care clinics, as well as between those attending clinics with high (>100 patients per clinician) versus low (≤100 patients per clinician) patient loads. Ethics approval for the analysis of these data for research purposes was provided by the Institutional Review Board of the National Center for AIDS/STD Control and Prevention (NCAIDS) at the Chinese Centers for Disease Control and Prevention. This analysis relied on an agreement between the Institutional Review Boards of NCAIDS and the University of North Carolina, Chapel Hill. Findings 3611 HIV-serodiscordant couples contributed a total of 21 231 person-years. Index partners received HIV care at 159 different HIV care centres distributed over three tiers of care, including village clinics (40·8%) township health centres (56·6%), and county hospitals (2·5%). 2961 (82%) of the 3611 serodiscordant couples lived within 10 km of their assigned HIV clinic, and 2654 (73%) attended clinics with patient-to-provider ratios of at least 100:1. In adjusted Cox models, attending clinics in which clinicians bore average patient loads of 100 or more increased HIV transmission risk (adjusted hazard ratio aHR 1·50, 95% CI 1·00–4·84), an effect amplified in village tier clinics (1·55, 1·23–6·78). Travel distance was associated with HIV transmission only after stratification; travelling medium distances to village clinics increased transmission risk (1·83, 1·04–3·21), whereas travelling longer distances to township or county-level clinics lowered transmission risk (0·10, 0·01–0·75). Interpretation High patient loads at HIV clinics was strongly associated with increased risk of HIV transmission in our population, particularly at village-level clinics. Increased travel distance had divergent effects based on clinic tier, suggesting unique mechanisms operating across levels of resource availability. The resource availability of long-term HIV treatment might place substantial strains on small rural clinics, for which investments in additional support staff or time-saving tools such as point-of-care laboratory testing might bring about impactful change in treatment outcomes. Funding Ministry of Science and Technology, People's Republic of China, National Institutes of Health of the USA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it ...delays HIV-1 disease progression is unknown. We investigated the effect of aciclovir on HIV-1 progression. Methods In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to aciclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per μL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per μL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per μL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00194519. Findings At enrolment, the median CD4 cell count was 462 cells per μL and median HIV-1 plasma RNA was 4·1 log10 copies per μL. Aciclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned aciclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio HR 0·84, 95% CI 0·71–0·98, p=0·03). In those with CD4 counts ≥350 cells per μL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per μL by 19% (0·81, 0·71–0·93, p=0·002) Interpretation The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. Funding Bill & Melinda Gates Foundation.
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Monocytes lack lactoferrin and have much less myeloperoxidase than neutrophils. They also acquire a potential catalyst for .OH production (tartrate-resistant acid phosphatase) as they differentiate ...into macrophages. Consequently, the nature of free radicals produced by these cells was examined using the previously developed spin-trapping system. When stimulated with either PMA or OZ neither monocytes nor monocyte-derived macrophages (MDM) exhibited spin trap evidence of .OH formation. Pretreatment with IFN-gamma failed to induce MDM .OH production. When provided with an exogenous Fe+3 catalyst, both stimulated monocytes and MDM, but not PMN, exhibited sustained .OH production, presumably due to the absence of lactoferrin in mononuclear phagocytes. Sustained production of .OH could contribute to the microbicidal activity of mononuclear phagocytes as well as inflammatory tissue damage under in vivo conditions where catalytic Fe+3 may be present.
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