Nivashnee Naicker

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C.BACKGROUND The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. METHODS We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. FINDINGS 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76-2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20,483 copies per mL (n=33) in the vaccine group and 34,032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. INTERPRETATION The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. FUNDING The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.

Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa

BACKGROUND Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. METHODS HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. RESULTS Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5-7.2)], clinical symptoms were not. CONCLUSIONS Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.

Challenges of diagnosing acute HIV-1 subtype C infection in African women: performance of a clinical algorithm and the need for point-of-care nucleic-acid based testing.

Background Prompt diagnosis of acute HIV infection (AHI) benefits the individual and provides opportunities for public health intervention. The aim of this study was to describe most common signs and symptoms of AHI, correlate these with early disease progression and develop a clinical algorithm to identify acute HIV cases in resource limited setting. Methods 245 South African women at high-risk of HIV-1 were assessed for AHI and received monthly HIV-1 antibody and RNA testing. Signs and symptoms at first HIV-positive visit were compared to HIV-negative visits. Logistic regression identified clinical predictors of AHI. A model-based score was assigned to each predictor to create a risk score for every woman. Results Twenty-eight women seroconverted after a total of 390 person-years of follow-up with an HIV incidence of 7.2/100 person-years (95%CI 4.5–9.8). Fifty-seven percent reported ≥1 sign or symptom at the AHI visit. Factors predictive of AHI included age <25 years (OR = 3.2; 1.4–7.1), rash (OR = 6.1; 2.4–15.4), sore throat (OR = 2.7; 1.0–7.6), weight loss (OR = 4.4; 1.5–13.4), genital ulcers (OR = 8.0; 1.6–39.5) and vaginal discharge (OR = 5.4; 1.6–18.4). A risk score of 2 correctly predicted AHI in 50.0% of cases. The number of signs and symptoms correlated with higher HIV-1 RNA at diagnosis (r = 0.63; p<0.001). Conclusions Accurate recognition of signs and symptoms of AHI is critical for early diagnosis of HIV infection. Our algorithm may assist in risk-stratifying individuals for AHI, especially in resource-limited settings where there is no routine testing for AHI. Independent validation of the algorithm on another cohort is needed to assess its utility further. Point-of-care antigen or viral load technology is required, however, to detect asymptomatic, antibody negative cases enabling early interventions and prevention of transmission.

Randomized Cross-Sectional Study to Compare HIV-1 Specific Antibody and Cytokine Concentrations in Female Genital Secretions Obtained by Menstrual Cup and Cervicovaginal Lavage

Introduction Optimizing methods for genital specimen collection to accurately characterize mucosal immune responses is a priority for the HIV prevention field. The menstrual cup (MC) has been proposed as an alternative to other methods including cervicovaginal lavage (CVL), but no study has yet formally compared these two methods. Methods Forty HIV-infected, antiretroviral therapy-naïve women from the CAPRISA 002 acute HIV infection cohort study were randomized to have genital fluid collected using the MC with subsequent CVL, or by CVL alone. Qualitative data, which assessed levels of comfort and acceptability of MC using a 5-point Likert scale, was collected. Luminex multiplex assays were used to measure HIV-specific IgG against multiple gene products and 48 cytokines. Results The majority (94%) of participants indicated that insertion, wearing and removal of the MC was comfortable. Nineteen MCs with 18 matching, subsequent CVLs and 20 randomized CVLs were available for analysis. Mucosal IgG responses against four HIV-antigens were detected in 99% of MCs compared to only 80% of randomized CVLs (p = 0.029). Higher specific antibody activity and total antibodies were observed in MCs compared to CVL (all p<0.001). In MCs, 42/48 (88%) cytokines were in the detectable range in all participants compared to 27/48 (54%) in CVL (p<0.001). Concentrations of 22/41 cytokines (53.7%) were significantly higher in fluid collected by MC. Both total IgG (r = 0.63; p = 0.005) and cytokine concentrations (r = 0.90; p<0.001) correlated strongly between MC and corresponding post-MC CVL. Conclusions MC sampling improves the detection of mucosal cytokines and antibodies, particularly those present at low concentrations. MC may therefore represent an ideal tool to assess immunological parameters in genital secretions, without interfering with concurrent collection of conventional CVL samples.

HIV disease progression in seroconvertors from the CAPRISA 004 tenofovir gel pre-exposure prophylaxis trial.

Background:Although antiretroviral pre-exposure prophylaxis prevents HIV acquisition, it is not known if it alters HIV disease progression. This study assesses whether tenofovir gel impacted on disease progression among CAPRISA 004 microbicide trial seroconvertors. Methods:Eighty-three seroconvertors from the tenofovir and placebo gel arms of the CAPRISA 004 trial were monitored prospectively for a minimum of 2 years by CD4 count and viral load (VL). Linear mixed models were fitted to HIV VL, and log rank test was used to compare time to reach CD4 counts of <350 cells per microliter. Results:Median 2-week postinfection VL was 4.74 and 4.45 log copies per milliliter in women assigned to tenofovir gel (n = 32) and placebo gel (n = 51) (P = 0.189). Corresponding 12-month postinfection VLs were 4.24 and 3.70 log copies per milliliter (P = 0.016). After adjusting for clinical and behavioral characteristics and protective HLA alleles, mean VLs within the first 2 years were 4.51 and 4.02 log copies per milliliter in women from the tenofovir and placebo arms (P = 0.013). Among women with vaginal tenofovir measurements, mean VLs were 4.53 and 4.60 log copies per milliliter in those with detectable versus undetectable levels (P = 0.840). Overall mean CD4 counts were 463 and 514 cells per microliter in women assigned to tenofovir and placebo (P = 0.290). Thirty-two women (38.6%) reached CD4 counts of <350 cells per microliter at median 9.4 months postinfection, 13 (40.6%) from the tenofovir and 19 (37.3%) from the placebo arms (P = 0.786). Conclusions:Tenofovir gel had no impact on postinfection CD4 counts or the rate of CD4 decline. Although seroconvertors from the tenofovir arm experienced higher VLs, this did not result in a need for earlier antiretroviral therapy.

Metabolic Syndrome After HIV Acquisition in South African Women.

Background:Noncommunicable diseases are common among chronically infected patients with HIV in the developed world, but little is known about these conditions in African cohorts. We assessed the epidemiology of metabolic syndrome among young South African women during the first 3 years after HIV acquisition. Methods:A total of 160 women were followed prospectively in the CAPRISA 002 Acute Infection study. Metabolic syndrome was defined as a constellation of hyperlipidemia, hypertension, hyperglycemia/diabetes, and abdominal obesity. Time trends were assessed using generalized estimation equation models. Results:Median age was 24 years and body mass index 27 kg/m2. Prevalence of metabolic syndrome at infection was 8.7% increasing to 19.2% over 36 months (P = 0.001). The proportion of women with body mass index >30 kg/m2 increased from 34.4% to 47.7% (P = 0.004), those with abnormal waist circumference and elevated blood pressure increased from 33.5% to 44.3% (P = 0.060) and 23.8% to 43.9% (P < 0.001), respectively. Incidence of metabolic syndrome was 9.13/100 person-years (95% CI: 6.02 to 13.28). Predictors of metabolic syndrome were age (per year increase odds ratio (OR) = 1.12; 95% CI: 1.07 to 1.16), time postinfection (per year OR = 1.47; 95% CI: 1.12 to 1.92), family history of diabetes (OR = 3.13; 95% CI: 1.71 to 5.72), and the human leukocyte antigen (HLA)-B*81:01 allele (OR = 2.95; 95% CI: 1.21 to 7.17), whereas any HLA-B*57 or B*58:01 alleles were protective (OR = 0.34; 95% CI: 0.15 to 0.77). HIV-1 RNA (OR = 0.89; 95% CI: 0.62 to 1.27) and CD4 count (OR = 1.03; 95% CI: 0.95 to 1.11) did not predict metabolic syndrome. Conclusions:The high burden of metabolic conditions in young South African HIV-infected women highlights the need to integrate noncommunicable disease and HIV care programs. Interventions to prevent cardiovascular disease must start at HIV diagnosis, rather than later during the disease course.

Beyond syndromic management: Opportunities for diagnosis-based treatment of sexually transmitted infections in low- and middle-income countries.

Introduction In light of the limited impact the syndromic management approach has had on the global sexually transmitted infection (STI) epidemic, we assessed a care model comprising point-of-care (POC) STI testing, immediate treatment, and expedited partner therapy (EPT) among a cohort of young women at high HIV risk in South Africa. Methods and findings HIV negative women presenting for STI care underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV), and swabs were sent for NG culture and susceptibility testing. Results were available within 2 hours and women with STIs were immediately treated and offered EPT packs, including medication, condoms, and information for sexual partners. An EPT questionnaire was administered after one week, and women retested for STIs after 6 and 12 weeks. 267 women, median age 23 (IQR 21–26), were recruited and 88.4% (236/267) reported genital symptoms. STI prevalence was CT 18.4% (95%CI 13.7–23.0), NG 5.2% (95%CI 2.6–7.9) and TV 3.0% (95%CI 1.0–5.0). After 12 weeks, all but one NG and two CT infections were cleared. No cephalosporin-resistant NG was detected. Of 63/267 women (23.6%) diagnosed with STIs, 98.4% (62/63) were offered and 87.1% (54/62) accepted EPT. At one week 88.9% (48/54) stated that their partner had taken the medication. No allergic reactions or social harms were reported. Of 51 women completing 6-week follow up, detection rates were lower amongst women receiving EPT (2.2%, 1/46) compared to those who did not (40.0%, 2/5), p = 0.023. During focus group discussions women supported the care model, because they received a rapid, specific diagnosis, and could facilitate their partners’ treatment. Conclusions POC STI testing and EPT were acceptable to young South African women and their partners, and could play an important role in reducing STI reinfection rates and HIV risk. Larger studies should evaluate the feasibility and cost-effectiveness of implementing this strategy at population level.

Efficacy and safety of tenofovir-containing antiretroviral therapy in women who acquired HIV while enrolled in tenofovir gel prophylaxis trials.

BACKGROUND We assessed whether women who acquired HIV during tenofovir gel prophylaxis trials can be safely and effectively treated with tenofovir-containing antiretroviral therapy (ART). METHODS Between May 2011 and October 2014, HIV seroconvertors from two tenofovir gel trials were recruited when eligible for ART (CD4+ T-cell count <350 cells/μl, pregnancy or AIDS-defining illness). Women were randomized to tenofovir-containing (tenofovir + lamivudine/emtricitabine + efavirenz) or tenofovir-sparing (zidovudine + lamivudine/emtricitabine + efavirenz) antiretroviral treatment regimens. The proportion with virological suppression, adverse events and drug switches were compared. RESULTS Fifty-nine women were enrolled and followed-up for median 18 months (IQR 6-24). Twenty-nine women (7 tenofovir gel exposed, 22 tenofovir gel unexposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed, 21 tenofovir gel unexposed) to a tenofovir-sparing regimen. Median baseline CD4+ T-cell count and viral load (VL) were 345 cells/μl (IQR 280-423) and 4.5 log copies/ml (sd 0.79), and did not differ by ART assignment. Overall VL suppression rates were 88.0% and 78.3% at 6 months (P=0.454) and 85.7% and 79.0% at 12 months (P=0.689) in women on the tenofovir-containing and tenofovir-sparing regimens, respectively. Toxicity-related drug switches were more frequent in women on the tenofovir-sparing than tenofovir-containing regimen (36.7% versus 0.0%, P<0.001). CONCLUSIONS Preliminary data show that tenofovir-containing ART was effective and more tolerable in HIV seroconvertors from tenofovir gel prophylaxis trials and may be considered for use in women with prior tenofovir gel exposure. Clinical trials.gov NCT01387022.

P14-07. Offering new prevention modalities in HIV vaccine trials: experience with male circumcision in the Phambili trial

Address: 1Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa, 2Centre for the AIDS Programme of Research in South Africa, Congella, South Africa, 3Statistical Center for HIV/AIDS Research and Prevention, Seattle, WA, USA, 4Aurum Institute for Health Research, Johannesburg, South Africa, 5Medunsa Clinical Research Unit, Tshwane, South Africa, 6Desmond Tutu HIV Foundation, University of Cape Town, Cape Town, South Africa, 7Center for the AIDS Programme of Research in South Africa, Congella, South Africa and 8Fred Hutchinson Cancer Research Center, Seattle, USA * Corresponding author

P3.166 High chlamydia and bacterial vaginosis burden in hiv epicentre in south africa

Introduction As long as syndromic management of sexually transmitted infections (STI) remains the main model of care in low and middle income countries, diagnostic surveillance is essential for STI control, especially in high HIV incidence settings. Here, we present the baseline data from the CAPRISA 083 cohort study that was conducted in a large urban primary health care clinic in KwaZulu-Natal, South Africa. Methods Women aged 18–40 presenting for syndromic STI care at the facility were assessed for participation. HIV positive women (prevalence 39.1%), pregnant women (9.1%) or those engaging in sex work were excluded due to pre-determined eligibility criteria. Women consenting to the study completed a sexual risk questionnaire, were examined by a nurse, and underwent point-of-care testing for chlamydia and gonorrhoea (Xpert CT/NG), trichomonas (OSOM rapid test), and microscopy to assess for bacterial vaginosis (BV) and candida. Gonorrhoea cases were further investigated for antibiotic resistance. Results A total of 267 women, median age 23 (IQR 21–27), were enrolled and 88.4% reported to be symptomatic. All were sexually active and 75.7% stated that they used condoms with their partners, although only 3.7% used them consistently. 125 (46.8%) had abnormal pelvic examinations, including 106 (39.7%) women with vaginal discharge. STI testing revealed an 18.5% prevalence of chlamydia (20.5% in <25 year-olds), 5.2% gonorrhoea and 2.6% trichomonas. Two thirds of women (69.3%) had evidence of abnormal vaginal flora (33.7% BV and 35.6% intermediate flora) based on Nugent Score, and 17.6% were diagnosed with candida infection. A total of 52/267 (19.5%) reported symptoms, but had no STI or abnormal flora found. Of 9 specimen cultured for gonorrhoea resistance, 7 (77.7%) were resistant to penicillin and 4 (44.4%) to ciprofloxacin, but no cephalosporin resistance was identified. Conclusion In this high HIV incidence setting, the burden of chlamydia infection and abnormal vaginal flora was concernedly high, warranting enhanced STI management strategies at population level. Support: This work was NIH-funded (AI116759). Cepheid loaned two 4-module Genexpert machines to the study team free-of-charge, but did not contribute to the preparation of this abstract