Use of Tenofovir Diphosphate Levels to Predict Viremia During the Postpartum Period in Women Living With Human Immunodeficiency Virus (HIV): A Nested Case-Control Study.

BACKGROUND: There are few data on the utility of tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs) to predict future viral load (VL) in postpartum women with HIV on antiretroviral therapy (ART). METHODS: We conducted a nested case-control study within a trial of postpartum ART delivery strategies. Participants started ART containing tenofovir disoproxil fumarate (TDF) in pregnancy, were <10 weeks postpartum, and had a VL <400 copies/mL. VL and TFV-DP samples were taken every 3-6 months over 24 months. Cases had ≥1 VL ≥20 copies/mL; controls were randomly sampled from women with persistent viral suppression (VS; VL <20 copies/mL). Generalized estimating equations were used to calculate likelihood odds ratios (LORs) for future VL ≥20 copies/mL by TFV-DP concentration at the preceding visit. RESULTS: 61 cases and 20 controls contributed 365 DBS-VL pairs (median ART duration, 16 months). Sensitivity and specificity of TFV-DP <700 fmol/punch to detect future viremia were 62.9% (95% CI, 54.7-70.6%) and 89.7% (84.9-93.4%), respectively. Adjusting for age, ART duration, previous VL, and duration between the TFV-DP and VL measures, LORs of viremia for TFV-DP concentrations 350-699 and <350 fmol/punch versus TFV-DP ≥1850 fmol/punch were 3.5 (95% CI, 1.1-10.8; P = .033) and 12.9 (3.6-46.6; P < .0001), respectively. Including only samples taken during VS, the LOR of future viremia for TFV-DP concentration <350 fmol/punch versus TFV-DP ≥1850 fmol/punch was 9.5 (1.9-47.0). CONCLUSIONS: TFV-DP concentrations in DBSs were strongly associated with future viremia and appear useful to identify nonadherence and predict future elevated VL.

Low prevalence of hepatitis B virus infection in HIV-uninfected pregnant women in Cape Town, South Africa: implications for oral pre-exposure prophylaxis roll out.

BACKGROUND: Oral daily preexposure prophylaxis (PrEP) using emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) is recommended as standard of care for prevention in individuals at high risk for HIV infection, including pregnant and postpartum cisgender women. FTC/TDF is also active against hepatitis B virus (HBV); however, concern has been raised that providing PrEP to individuals infected with HBV could lead to hepatitis flares and liver injury, especially in the setting of suboptimal PrEP use. METHODS: We conducted a cross-sectional analysis of baseline data from the PrEP in pregnant and postpartum women (PrEP-PP) cohort study from February 2020-March 2022 in one antenatal care clinic in Cape Town, South Africa (SA) to evaluate: (1) the field performance of a point of care test (POCT) (Determine II, Abbott Inc., Japan) for diagnosis of hepatitis B surface antigen (HBsAg) in a maternity setting, (2) the prevalence of HBV in a cohort of pregnant women not living with HIV. RESULTS: We enrolled 1194 HIV sero-negative pregnant women at their first antenatal visit. Median age was 26 years (IQR = 22-31 years); 52% were born before 1995 (before universal HBV vaccination had started in South Africa). Median gestational age was 22 weeks (IQR = 16-30 weeks). There were 8 POCT and laboratory confirmed HBV cases among 1194 women. The overall prevalence of 0.67% (95% CI = 0.34-1.32%). In women born before 1995, 8 of 622 women were diagnosed with HBsAg; the prevalence was 1.29% (95% CI = 0.65-2.52%), and in women born in 1995 or after (n = 572); the prevalence was 0% (95% CI = 0.0-0.67%). We confirmed the test results in 99.8% of the rapid HBsAg (Determine II). Sensitivity was 100% (95% CI = 68-100%). Specificity was 100% (95% CI = 99.67-100%). CONCLUSION: The prevalence of HBV was very low in pregnant women not living with HIV and was only in women born before the HBV vaccine was included in the Expanded Program of Immunization. The Determine II POCT HBsAg showed excellent performance against the laboratory assay. HBV screening should not be a barrier to starting PrEP in the context of high HIV risk communities.

Improved virologic outcomes in postpartum women living with HIV referred to differentiated models of care.

OBJECTIVES: Differentiated service delivery (DSD) models are used to deliver antiretroviral therapy (ART) but data are limited in postpartum women, who are at high risk of non-adherence and elevated viral load (VL) over the extended postpartum period. DESIGN: Randomized controlled trial. METHODS: We enrolled consecutive postpartum women who initiated ART during pregnancy and met local DSD eligibility (clinically stable, VL less than 400 copies/ml) at a large primary healthcare (PHC) clinic. Women were randomized to a community-based 'adherence club' (AC, the local DSD model: community health worker-led groups of 20-30 patients with ART dispensing at a community venue) or routine PHC clinics (local standard of care with nurse/doctor-led services). Follow-up visits with VL separate from routine care took place at 3, 6, 12, 18 and 24 months postpartum. Endpoints were time to VL of at least 1000 copies/ml (primary) and VL of at least 50 copies/ml (secondary) by intention-to-treat. RESULTS: At enrolment ( n  = 409), the median duration postpartum was 10 days, all women had a VL less than 1000 copies/ml and 88% had a VL less than 50 copies/ml; baseline characteristics did not differ by arm. Twenty-four-month retention was 89%. Sixteen and 29% of women in AC experienced a VL of at least 1000 copies/ml by 12 and 24 months, compared to 23 and 37% in PHC, respectively (hazard ratio [HR] = 0.71; 95% confidence interval [CI] = 0.50-1.01). Thirty-two and 44% of women in ACs had a VL of at least 50 copies/ml by 12 and 24 months, compared to 42 and 56% in PHC, respectively (HR = 0.68; 95% CI = 0.51-0.91). CONCLUSIONS: Early DSD referral was associated with reduced viraemia through 24 months postpartum and may be an important strategy to improve maternal virologic outcomes.

72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study.

BACKGROUND: Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. METHODS: DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0-5·1) in the dolutegravir group compared with 12·1 weeks (10·7-13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5-2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. INTERPRETATION: Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. FUNDING: Unitaid.

Risk-based screening to identify reproductive tract infection among HIV-infected women desiring use of intrauterine contraceptives.

BACKGROUND: Reproductive tract infections (RTIs) are a major cause of morbidity and mortality, yet RTI testing remains limited in resource-constrained settings. We assessed performance of an existing RTI risk assessment screening tool among women living with HIV (WLHIV) considering intrauterine contraceptive (IUC) use. METHODS: We conducted a cross-sectional analysis among WLHIV screened for participation in an IUC trial in Cape Town, South Africa (NCT01721798). RTI testing included Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and bacterial vaginosis. Tool scoring was based on five separately scored criteria: (1) age under 25 years, (2) cohabitation with a partner, (3) secondary education, (4) self-reported intermenstrual bleeding and (5) number of current sexual partners and condom use frequency (score 0-5). We assessed tool performance in detecting RTI at 0 vs 1-5, 0-1 vs 2-5 and 0-2 vs 3-5 score thresholds. RESULTS: Of 303 women, 52% (n=157) reported antiretroviral therapy use and median age was 31 years. The prevalence of any RTI was 38% (gonorrhoea=7%, chlamydia=11%, trichomoniasis=12% and bacterial vaginosis=18%) and 8% of women had multiple RTIs. Overall, 4%, 27% and 69% of women had screening tool scores of 0, 1 or 2+, respectively. At a threshold of at least one scored criterion, the tool demonstrated high sensitivities (95%-97%) but low specificities (3%-4%) for detecting any RTI. Increasing the score threshold and/or inclusion of abnormal vaginal discharge marginally improved specificity. CONCLUSION: The prevalence of RTIs observed in this population was high, and the screening tool had no discriminatory power to detect prevalent RTIs.

ART Adherence, Resistance, and Long-term HIV Viral Suppression in Postpartum Women.

HIV+ South African women who achieved viral suppression during routine antenatal care, but later experienced a viremic episode (viral load >1000 copies/mL), were examined for presence of antiretrovirals and classified as "nonadherers" or "suboptimal adherers." Women were tested for drug resistance mutations (DRMs) at several time points and underwent viral load testing 36-60 months postpartum. Suboptimal adherers were more likely to have DRM detected during their viremic episode (P = .03) and at a subsequent viremic time point (P = .05). There was no difference in levels of viral suppression 36-60 months later in women with DRM detected vs women who had no evidence of DRM (P = .5).

A Comparison of Plasma Efavirenz and Tenofovir, Dried Blood Spot Tenofovir-Diphosphate, and Self-Reported Adherence to Predict Virologic Suppression Among South African Women.

BACKGROUND: Tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) is an objective long-term adherence measure, but data are limited on its ability to predict virologic suppression (VS) in people on antiretroviral (ARV) treatment. There are also no data comparing DBS TFV-DP with plasma ARV concentrations as predictors of VS. METHODS: Women who were on a first-line regimen of tenofovir, emtricitabine, and efavirenz (EFV) were enrolled in a cross-sectional study. Plasma EFV and tenofovir (TFV), DBS TFV-DP assays, and 30-day self-reported adherence were evaluated as predictors of VS (<50 copies/mL) with the area under the curve of receiver operating characteristics and logistic regression. RESULTS: We enrolled 137 women; mean age of 33 years; median 4 years on antiretroviral therapy; 88 (64%) had VS. In receiver operating characteristics analyses: DBS TFV-DP [0.926 (95% CI: 0.876 to 0.976)] had a higher area under the curve than plasma TFV [0.864 (0.797 to 0.932); P = 0.006], whereas plasma EFV [0.903 (0.839-0.967)] was not significantly different from DBS TFV-DP (P = 0.138) or plasma TFV (P = 0.140); all ARV assays performed better than self-report. The association of TFV-DP in DBS with VS strengthened with increasing concentrations [reference <350 fmol/punch: 350-699 fmol/punch aOR 37 (8-178); 700-1249 fmol/punch aOR 47 (13-175); ≥1250 fmol/punch aOR 175 (20-1539)]. "White coat adherence" (defined as DBS TFV-DP <350 fmol/punch with detectable plasma TFV) was only detected in 4 women. CONCLUSIONS: Plasma EFV, TFV, and DBS TFV-DP were all strong predictors of VS. EFV or TFV assays have potential for development as point-of-care assays for use as objective adherence measures in resource-limited settings.

High human papillomavirus (HPV) prevalence in South African adolescents and young women encourages expanded HPV vaccination campaigns.

The objectives of the study were to investigate prevalence of cervical human papillomavirus (HPV) genotypes to inform HPV vaccination strategy in South Africa and to study factors associated with HPV prevalence. Sexually active, HIV-negative women, aged 16-22 years recruited from Soweto (n = 143) and Cape Town (n = 148) were tested for cervical HPV and other genital infections. Overall HPV prevalence was 66.7% (194/291) in young women. Cape Town women were more likely to have multiple HPV infections than the Soweto women (48.0%, 71/148 versus 35.0%, 50/143 respectively, p = 0.033) and probable HR-HPV types (34.5%, 51/148 versus 21.7%, 31/143 respectively, p = 0.022). The most frequently detected HPV types were HPV-16 (11.7%), HPV-58 (10.3%), HPV-51 (8.9%), HPV-66 (8.6%), HPV-18 and HPV-81 (7.6% each). HPV types targeted by the bivalent HPV vaccine (HPV-16/18) were detected in 18.6% (54/291) of women, while those in the quadrivalent vaccine (HPV-6/11/16/18) were detected in 24.7% (72/291) of women; and those in the nonavalent vaccine (HPV-6/11/16/18/31/33/45/52/58) were detected in 38.5% (112/291) of women. In a multivariable analysis, bacterial vaginosis remained significantly associated with HPV infection (OR: 4.0, 95% CI: 1.4-12.6). Women were more likely to be HPV positive if they had received treatment for STI during the past 6-months (OR: 3.4, 95% CI: 1.1-12.4) or if they had ever been pregnant (OR: 2.3, 95% CI: 1.1-5.5). Compared to women who reported only one sexual partner, those with increased number of lifetime sex partners were more likely to have HPV (4-10 partners: OR: 2.9, 95% CI: 1.1-8.0). The high prevalence of HPV types targeted by the nonavalent HPV vaccine encourages the introduction of this vaccine and catch-up HPV vaccination campaigns in South Africa. The high burden of BV and concurrent STIs also highlights the need to improve the prevention and appropriate management of sexually-acquired and other genital tract infections in South African youth.