Nora E. Rosenberg

Role of acute and early HIV infection in the sexual transmission of HIV.

Purpose of reviewAcute HIV infection (AHI), the earliest period after HIV acquisition, is only a few weeks in duration. In this brief period, the concentration of HIV in blood and genital secretions is extremely high, increasing the probability of HIV transmission. Although a substantial role of AHI in the sexual transmission of HIV is biologically plausible, the significance of AHI in the epidemiological spread of HIV remains uncertain. Recent findingsAHI is diagnosed by detecting viral RNA or antigen in the blood of persons who are HIV seronegative. Depending on the setting, persons with AHI represent between 1 and 10% of persons with newly diagnosed HIV infection. The high concentration of virus during AHI leads to increased infectiousness, possibly as much as 26 times greater than during chronic infection. In mathematical models, the estimated proportion of transmission attributed to AHI has varied considerably, depending on model structure, model parameters, and the population. Key determinants include the stage of the HIV epidemic and the sexual risk profile of the population. SummaryDespite its brief duration, AHI plays a disproportionate role in the sexual transmission of HIV infection. Detection of persons with AHI may provide an important opportunity for transmission prevention.

Detection of Acute HIV Infection: A Field Evaluation of the Determine® HIV-1/2 Ag/Ab Combo Test

BACKGROUND Most human immunodeficiency virus (HIV) point-of-care tests detect antibodies (Ab) but not p24 antigen (Ag) or RNA. In the absence of antibodies, p24 antigen and RNA typically indicate acute HIV infection. We conducted a field evaluation of the Determine® HIV-1/2 Ag/Ab Combo rapid test (Combo RT). METHODS The antigen portion of the Combo RT (for acute HIV infection) was compared with a Roche Monitor HIV RNA polymerase chain reaction assay. The antibody portion of Combo RT (for established HIV infection) was compared with rapid test algorithms. Participants were enrolled at a sexually transmitted infection clinic and HIV testing and counseling center in Lilongwe, Malawi. Rapid testing was conducted with parallel testing in the clinic and serial testing in the center. The Combo RT was performed in clinic participants with negative or discordant antibody results and in all center participants. RESULTS Of the participants 838 were HIV negative, 163 had established HIV infection, and 8 had acute HIV infection. For detecting acute HIV infection, the antigen portion had a sensitivity of 0.000 and a specificity of 0.983. For detecting established HIV infection, the antibody portion had a sensitivity of 0.994 and a specificity of 0.992. CONCLUSIONS Combo RT displayed excellent performance for detecting established HIV infection and poor performance for detecting acute HIV infection. In this setting, Combo RT is no more useful than current algorithms.

HIV testing and counseling leads to immediate consistent condom use among South African stable HIV-discordant couples.

Objective:Effective behavioral HIV prevention is needed for stable HIV-discordant couples at risk for HIV, especially those without access to biomedical prevention. This analysis addressed whether HIV testing and counseling with ongoing counseling and condom distribution lead to reduced unprotected sex in HIV-discordant couples. Methods:Partners in Prevention HSV/HIV Transmission Study was a randomized trial conducted from 2004 to 2008 assessing whether acyclovir reduced HIV transmission from HSV-2/HIV-1–coinfected persons to HIV-uninfected sex partners. This analysis relied on self-reported behavioral data from 508 HIV-infected South African participants. The exposure was timing of first HIV testing and counseling: 0–7, 8–14, 15–30, or >30 days before baseline. In each exposure group, predicted probabilities of unprotected sex in the last month were calculated at baseline, month 1, and month 12 using generalized estimating equations with a logit link and exchangeable correlation matrix. Results:At baseline, participants who knew their HIV status for less time experienced higher predicted probabilities of unprotected sex in the last month: 0–7 days, 0.71; 8–14 days, 0.52; 15–30 days, 0.49; >30 days, 0.26. At month 1, once all participants had been aware of being in HIV-discordant relationships for ≥1 month, predicted probabilities declined: 0–7 days, 0.08; 8–14 days, 0.08; 15–30 days, 0.15; >30 days, 0.14. Lower predicted probabilities were sustained through month 12: 0–7 days, 0.08; 8–14 days, 0.11; 15–30 days, 0.05; >30 days, 0.19. Conclusions:Unprotected sex declined after HIV-positive diagnosis and declined further after awareness of HIV discordance. Identifying HIV-discordant couples for behavioral prevention is important for reducing HIV transmission risk.

Recruiting male partners for couple HIV testing and counselling in Malawi's option B+ programme: An unblinded randomised controlled trial

BACKGROUND Couples HIV testing and counselling (CHTC) is encouraged but is not widely done in sub-Saharan Africa. We aimed to compare two strategies for recruiting male partners for CHTC in Malawis option B+ prevention of mother-to-child transmission programme: invitation only versus invitation plus tracing and postulated that invitation plus tracing would be more effective. METHODS We did an unblinded, randomised, controlled trial assessing uptake of CHTC in the antenatal unit at Bwaila District Hospital, a maternity hospital in Lilongwe, Malawi. Women were eligible if they were pregnant, had just tested HIV-positive and therefore could initiate antiretroviral therapy, had not yet had CHTC, were older than 18 years or 16-17 years and married, reported a male sex partner in Lilongwe, and intended to remain in Lilongwe for at least 1 month. Women were randomly assigned (1:1) to either the invitation only group or the invitation plus tracing group with block randomisation (block size=4). In the invitation only group, women were provided with an invitation for male partners to present to the antenatal clinic. In the invitation plus tracing group, women were provided with the same invitation, and partners were traced if they did not present. When couples presented they were offered pregnancy information and CHTC. Women were asked to attend a follow-up visit 1 month after enrolment to assess social harms and sexual behaviour. The primary outcome was the proportion of couples who presented to the clinic together and received CHTC during the study period and was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02139176. FINDINGS Between March 4, 2014, and Oct 3, 2014, 200 HIV-positive pregnant women were enrolled and randomly assigned to either the invitation only group (n=100) or the invitation plus tracing group (n=100). 74 couples in the invitation plus tracing group and 52 in the invitation only group presented to the clinic and had CHTC (risk difference 22%, 95% CI 9-35; p=0.001) during the 10 month study period. Of 181 women with follow-up data, two reported union dissolution, one reported emotional distress, and none reported intimate partner violence. One male partner, when traced, was confused about which of his sex partners was enrolled in the study. No other adverse events were reported. INTERPRETATION An invitation plus tracing strategy was highly effective at increasing CHTC uptake. Invitation plus tracing with CHTC could have many substantial benefits if brought to scale. FUNDING National Institutes of Health.

How can we better identify early HIV infections

Purpose of reviewDetection of early HIV infections (EHIs), including acute HIV infection (AHI), is important for individual health, prevention of HIV transmission, and measurement of HIV incidence. We describe markers of EHI, diagnostic strategies for detecting these markers, and ways to incorporate these strategies into diagnostic and HIV incidence algorithms. Recent findingsFor individual diagnosis in the USA and Europe, laboratory-based diagnostic algorithms increasingly incorporate fourth-generation HIV antigen tests, allowing for earlier detection. In some sub-Saharan African settings, symptom-based screening is being explored to identify subsets of persons at high risk for AHI. Point-of-care diagnostics designed for AHI detection are in the pipeline and, if validated, represent an opportunity for real-time AHI diagnosis. At the population level, multiassay algorithms are promising new strategies for estimating HIV incidence on the basis of several assays applied to cross-sectional samples. These algorithms can be developed to optimize performance, in addition to cost and logistical considerations. SummaryThere are important recent advances in detection of EHIs at the individual and population levels. Applying optimal combinations of tests in diagnostic and HIV incidence algorithms is urgently needed to support the multiple goals derived from enhanced detection and discrimination of EHIs.

Improving PMTCT uptake and retention services through novel approaches in peer-based family-supported care in the clinic and community: a 3-arm cluster randomized trial (PURE Malawi).

Abstract:In July 2011, Malawi introduced an ambitious public health program known as “Option B+,” which provides all HIV-infected pregnant and breastfeeding women with lifelong combination antiretroviral therapy, regardless of clinical stage or CD4 count. Option B+ is expected to have benefits for HIV-infected women, their HIV-exposed infants, and their HIV-uninfected male sex partners. However, these benefits hinge on early uptake of prevention of mother-to-child transmission, good adherence, and long-term retention in care. The Prevention of mother-to-child transmission Uptake and REtention (PURE) study is a 3-arm cluster randomized controlled trial to evaluate whether clinic- or community-based peer support will improve care-seeking and retention in care by HIV-infected pregnant and breastfeeding women, their HIV-exposed infants, and their male sex partners, and ultimately improve health outcomes in all 3 populations. We describe the PURE Malawi Consortium, the initial work conducted to inform the trial and interventions, the trial design, and the analysis plan. We then discuss concerns and expected contributions to Malawi and the region.

Assessing the effect of HIV counselling and testing on HIV acquisition among South African youth.

Objective:Youth aged 15–24 years in sub-Saharan Africa are at a high risk for HIV acquisition and urgently need HIV prevention interventions. HIV counselling and testing (HCT) is designed to promote HIV prevention. However the impact of HCT on HIV acquisition has never been assessed among youth. We assess the impact of HCT on HIV acquisition among South African youth. Design:Data came from an annual HIV survey for persons aged 15 years and over, nested within a socio-demographic household surveillance in a geographically defined area of KwaZulu-Natal. Within this population, we used data from 2006 to 2011 to construct a cohort of HIV-uninfected youth aged 15–24 years. Methods:We compared youth who reported knowing their HIV status from HCT with those who reported not knowing their HIV status for time to HIV seroconversion using time-varying marginal structural Cox proportional hazards models. Results:The cohort included 3959 HIV-uninfected youth, of whom 1167 (29%) reported HCT at baseline and an additional 1064 (27%) reported HCT during follow up. Youth experienced 248 seroconversions over 8536 person-years, an incidence rate of 2.91 per 100 person-years [95% confidence interval (CI) 2.56–3.28]. In crude analysis, HCT was not associated with HIV incidence (hazard ratio 1.02, 95% CI 0.79–1.31], but in marginal structural models weighted for risk factors, HCT was protective (hazard ratio 0.59, 95% CI 0.45–0.78). Conclusion:In this high-risk population, after accounting for differences in underlying HIV acquisition risk, HCT was associated with lower HIV incidence. HCT scale-up may have prevention benefits for HIV-uninfected youth.

Outcomes for paediatric Burkitt lymphoma treated with anthracycline-based therapy in Malawi

Burkitt lymphoma (BL) is the most common paediatric cancer in sub‐Saharan Africa (SSA). Anthracyline‐based treatment is standard in resource‐rich settings, but has not been described in SSA. Children ≤18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9·2 years (interquartile range 7·7–11·8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen‐month overall survival was 29% (95% confidence interval [CI] 18–41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2·13, 95% CI 1·15–3·94], female gender (HR 2·12, 95% CI 1·12–4·03), stage (HR 1·52 per unit, 95% CI 1·07–2·17), lactate dehydrogenase (HR 1·03 per 100 iu/l, 95% CI 1·01–1·05), albumin (HR 0·96 per g/l, 95% CI 0·93–0·99) and performance status (HR 0·78 per 10‐point increase, 95% CI 0·69–0·89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi.

Exploring the experiences of women and health care workers in the context of PMTCT Option B Plus in Malawi.

Introduction: Malawi has embarked on a “test-and-treat” approach to prevent mother-to-child transmission (PMTCT) of HIV, known as “Option B+,” offering all HIV-infected pregnant and breastfeeding women lifelong antiretroviral therapy (ART) regardless of CD4 count or clinical stage. A cross-sectional qualitative study was conducted to explore early experiences surrounding “Option B+” for patients and health care workers (HCWs) in Malawi. Methods: Study participants were purposively selected across 6 health facilities in 3 regional health zones in Malawi. Semi-structured interviews were conducted with women enrolled in “Option B+” (n = 24), and focus group discussions were conducted with HCWs providing Option B+ services (n = 6 groups of 8 HCWs). Data were analyzed using a qualitative thematic coding framework. Results: Patients and HCWs identified the lack of male involvement as a barrier to retention in care and expressed concerns at the rapidity of the test-and-treat process, which makes it difficult for patients to “digest” a positive diagnosis before starting ART. Fear regarding the breach of privacy and confidentiality were also identified as contributing to loss to follow-up of women initiated under the Option B+. Disclosure remains a difficult process within families and couples. Lifelong ART was also perceived as an opportunity to plan future pregnancies. Conclusions: As “Option B+” continues to be rolled out, novel interventions to support and retain women into care must be implemented. These include providing space, time, and support to accept a diagnosis before starting ART, engaging partners and families, and addressing the need for peer support and confidentiality.

STI Patients Are Effective Recruiters of Undiagnosed Cases of HIV: Results of a Social Contact Recruitment Study in Malawi

Background:Patients with newly diagnosed HIV may be part of social networks with elevated prevalence of undiagnosed HIV infection. Social network recruitment by persons with newly diagnosed HIV may efficiently identify undiagnosed cases of HIV infection. We assessed social network recruitment as a strategy for identifying undiagnosed cases of HIV infection. Methods:In a sexually transmitted infection (STI) clinic in Lilongwe, Malawi, 3 groups of 45 “seeds” were enrolled: STI patients with newly diagnosed HIV, STI patients who were HIV-uninfected, and community controls. Seeds were asked to recruit up to 5 social “contacts” (sexual or nonsexual). Mean number of contacts recruited per group was calculated. HIV prevalence ratios (PRs) and number of contacts needed to test to identify 1 new case of HIV were compared between groups using generalized estimating equations with exchangeable correlation matrices. Results:Mean number of contacts recruited was 1.3 for HIV-infected clinic seeds, 1.8 for HIV-uninfected clinic seeds, and 2.3 for community seeds. Contacts of HIV-infected clinic seeds had a higher HIV prevalence (PR: 3.2, 95% confidence interval: 1.3 to 7.8) than contacts of community seeds, but contacts of HIV-uninfected clinic seeds did not (PR: 1.1, 95% confidence interval: 0.4 to 3.3). Results were similar when restricted to nonsexual contacts. To identify 1 new case of HIV, it was necessary to test 8 contacts of HIV-infected clinic seeds, 10 contacts of HIV-uninfected clinic seeds, and 18 contacts of community seeds. Conclusions:Social contact recruitment by newly diagnosed STI patients efficiently led to new HIV diagnoses. Research to replicate findings and guide implementation is needed.