Preexposure prophylaxis for HIV infection among African women.

BACKGROUND: Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety. RESULTS: HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. CONCLUSIONS: Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).

Targeted solutions to increase dolutegravir coverage, viral load testing coverage, and viral suppression among children living with HIV in Togo: An analysis of routine facility data.

BACKGROUND: According to UNAIDS, Togo halved AIDS-related deaths among children ages 0-14 from 2010 to 2020. However, available data show low dolutegravir (DTG)-containing antiretroviral therapy (ART) coverage and low viral load suppression (VLS) among children living with HIV (CLHIV). We analyzed routine facility data before and after implementation of root-cause-based solutions for improving DTG coverage, viral load (VL) testing coverage, and VLS among CLHIV. DESCRIPTION: We analyzed routine data for CLHIV ≤14 years from October 2019 through September 2022. We assessed proportion of CLHIV on ART receiving DTG, VL testing coverage (CLHIV on ART with documented VL test result), and VLS (CLHIV with documented VL test result of <1,000 copies among those with test result). From October 2019 to September 2020, 52% were on a DTG-containing regimen, 48% had documented VL test results, and 64% had VLS. Site-level teams conducted a root-cause analysis and designed corresponding solutions implemented beginning October 2020: line listing and contacting eligible CLHIV to start/transition to DTG-containing regimen and collect VL samples; ART adherence support; monthly DTG stock monitoring; tracking pending VL test results through laboratory focal persons; documenting VL test results; and informing caregivers within one week if CLHIV not virally suppressed. Granular data were used to prioritize technical assistance to sites with lowest DTG coverage, VL testing coverage, and VLS. RESULTS: From baseline (October 2019-September 2020) to endline (October 2021-September 2022), increases were observed for DTG coverage (52% to 71%), VL testing coverage (48% to 90%), and VLS (64% to 82%). Age-disaggregated data showed positive trends. CONCLUSIONS: Root-cause-based solutions and granular data use increased DTG coverage, resulting in increased VL testing and VLS among CLHIV. These interventions should be scaled and become the national standard of care.

Use of service data to inform pediatric HIV-free survival following prevention of mother-to-child transmission programs in rural Malawi.

BACKGROUND: Recent years have seen rapid and significant progress in science and implementation of programs to prevent mother-to-child transmission of HIV. Programs that support PMTCT routinely monitor service provision but very few have measured their effectiveness. The objective of the study was to use service data to inform HIV-free survival among HIV exposed children that received antiretroviral drugs to prevent mother-to-child transmission (PMTCT) of HIV. The study was conducted in two rural districts in Malawi with support from FHI 360. METHODS: A descriptive observational study of PMTCT outcomes was conducted between June 2005 and June 2009. The dataset included patient-level data of all pregnant women 1) that tested HIV-positive, 2) that were dispensed with antiretroviral prophylaxis, and 3) whose addresses were available for home visits. The data were matched to each woman's corresponding antenatal clinic data from home visit registers. RESULTS: Out of 438 children whose home addresses were available, 33 (8%) were lost to follow-up, 35 (8%) were alive but not tested for HIV by the time home visit was conducted, and 52 (12%) were confirmed deceased. A total of 318 children were alive at the time of the home visit and had an HIV antibody test done at median age 15 months. The resulting estimated 24-month probability of HIV-free survival over all children was 78%. Among children who did not receive nevirapine, the estimated 24-month probability of HIV-free survival was 61%, and among those who did receive NVP syrup the estimate was 82%. CONCLUSIONS: When mothers and newborns received nevirapine, the estimated 24-month probability of HIV-free survival among children was high at 82% (CI: 54% to 99%). However this conclusion should be interpreted cautiously 1) due to the wide confidence interval; and 2) because the confidence interval range includes 55%, which is the natural HIV-free survival rate in the absence of a PMTCT intervention. This analysis highlighted the need of quality data and well-structured home visits to assess PMTCT effectiveness.

Infant feeding options, other nonchemoprophylactic factors, and mother-to-child transmission of HIV in Zambia.

BACKGROUND: The role of antiretroviral drugs in the prevention of mother-to-child transmission (PMTCT) of HIV is well known. The objective of this study is to explore how nonchemoprophylactic factors, including infant feeding practices, mother's HIV status disclosure, mode and place of delivery, infant gender, and maternal age, are related to MTCT. METHODS: The study analyzed program data of DNA polymerase chain reaction (PCR) results from dried blood spot samples and selected client information from perinatally exposed infants aged 0 to 12 months. RESULTS: A total of 8237 samples were analyzed. In all, 84% of the mothers ever breast-fed their children. In instances where both mother and baby received intervention, the transmission rates of HIV were higher among those who are still breast-feeding after 6 to 12 months. Disclosure, location, and mode of delivery did not have an effect on the transmission rates of HIV when both mother and baby received prophylaxis. CONCLUSION: Nonchemoprophylaxis factors, especially breast-feeding, play a key role in perinatal transmission of HIV.

Prevention of mother-to-child transmission of HIV in Zambia: implementing efficacious ARV regimens in primary health centers.

BACKGROUND: Safety and effectiveness of efficacious antiretroviral (ARV) regimens beyond single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT) have been demonstrated in well-controlled clinical studies or in secondary- and tertiary-level facilities in developing countries. This paper reports on implementation of and factors associated with efficacious ARV regimens among HIV-positive pregnant women attending antenatal clinics in primary health centers (PHCs) in Zambia. METHODS: Blood sample taken for CD4 cell count, availability of CD4 count results, type of ARV prophylaxis for mothers, and additional PMTCT service data were collected for HIV-positive pregnant women and newborns who attended 60 PHCs between April 2007 and March 2008. RESULTS: Of 14,815 HIV-positive pregnant women registered in the 60 PHCs, 2,528 (17.1%) had their CD4 cells counted; of those, 1,680 (66.5%) had CD4 count results available at PHCs; of those, 796 (47.4%) had CD4 count

HIV Retesting of HIV-Negative Pregnant Women in the Context of Prevention of Mother-to-Child Transmission of HIV in Primary Health Centers in Rural Zambia: What Did We Learn?

BACKGROUND: This observational study describes implementation of HIV retesting of HIV-negative women in prevention of mother-to-child transmission (PMTCT) services in Zambia. METHODS: Uptake of retesting and PMTCT services were compared across age, parity, and weeks of gestation at the time of the first HIV test, antiretrovirals regime, and HIV early diagnosis results from infants born to HIV-positive mothers. RESULTS: A total of 19 090 pregnant women were tested for HIV at their first antenatal visit, 16 838 tested HIV-negative and were offered retesting 3 months later: 11 339 (67.3%) were retested; of those, 55 (0.5%) were HIV positive. Uptake of the PMTCT package by women HIV positive at retest was not different but HIV-exposed infants born to women who retested HIV positive were infected at a higher rate (11.1%) compared to those born to women who tested HIV positive at their initial test (3.2%). CONCLUSION: We suggest rigorously (1) measuring the proportion of MTCT attributable to women who seroconvert during pregnancy and possibly adjust PMTCT approaches and (2) addressing the substantial loss to follow-up of HIV-negative pregnant women before HIV retesting.

Progress toward elimination of perinatal HIV transmission in Kenya: Analysis of early infant diagnosis data.

Interrupting vertical transmission of HIV from mothers to infants provides opportunity to transform the HIV/AIDS epidemic by eliminating new infections among children. We estimate mother-to-child transmission rates of infants born to known HIV-positive mothers offered prevention of mother-to-child transmission interventions and provide an indication of Kenya's progress toward elimination of perinatal transmission. We obtained from the Kenya National Early Infant Diagnosis (EID) database, all 131,451 DNA polymerase chain reaction test results of HIV-exposed infants aged 0-18 months who had dried blood spot samples taken between January 2008 and October 2013. The majority of samples were from infants aged 0-6 months (81.0%). Infants aged 6-12 months comprised 15.5%, while those aged 12-18 months were 3.5%. Overall, 11,439 (8.7%) were HIV-positive. Positivity rates were higher among older age groups: 6.8, 14.6, and 27.5% in age groups 0-6 months, 6-12 months, and 12-18 months old, respectively. In Kenya, scale-up and decentralization to primary health centers of EID services has been remarkable. Both increasing HIV-positivity trends in age groups 12-18 months and differences between provinces require further interrogation. Although significant, declining HIV-positivity trends in age groups 0-6 months and 6-12 months old observed between 2008 and 2013 is insufficient to achieve the elimination agenda.

Playing the Catch-Up Game: Accelerating the Scale-Up of Prevention of Mother-To-Child Transmission of HIV (PMTCT) Services to Eliminate New Pediatric HIV Infection in Nigeria.

INTRODUCTION: As the world is making progress towards elimination of mother-to-child transmission of HIV, poor coverage of PMTCT services in Nigeria remains a major challenge. In order to address this, scale-up was planned with activities organized into 3 phases. This paper describes the process undertaken in eight high burden Nigerian states to rapidly close PMTCT coverage gaps at facility and population levels between February 2013 and March 2014. METHODS: Activities were grouped into three phases-pre-assessment phase (engagement of a wide range of stakeholders), assessment (rapid health facility assessment, a cross sectional survey using mixed methods conducted in the various states between Feb and May 2013 and impact modelling), and post-assessment (drawing up costed state operational plans to achieve eMTCT by 2015, data-driven smart scale-up). RESULTS: Over a period of 10 months starting June 2013, 2044 facilities were supported to begin provision of PMTCT services. This increased facility coverage from 8% to 50%. A 246% increase was also recorded in the number of pregnant women and their families who have access to HIV testing and counselling in the context of PMTCT. Similarly, access to antiretrovirals for PMTCT has witnessed a 152% increase in these eight states between October 2013 and October 2014. CONCLUSION: A data-driven and participatory approach can be used to rapidly scale-up PMTCT services at community and facility levels in this region. These results present us with hope for real progress in Nigeria. We are confident that the efforts described here will contribute significantly to eliminating new pediatric HIV infection in Nigeria.

A systematic review of interventions to improve prevention of mother-to-child HIV transmission service delivery and promote retention.

INTRODUCTION: The success of prevention of mother-to-child transmission of HIV (PMTCT) is dependent upon high retention of mother-infant pairs within these programmes. This is a systematic review to evaluate the effectiveness of interventions that aim to improve PMTCT service delivery and promote retention throughout the PMTCT steps. METHODS: Selected databases were searched for studies published in English (up to September 2015). Outcomes of interest included antiretroviral (ARV) drugs or antiretroviral therapy (ART) initiation among HIV-positive pregnant and/or breastfeeding women and their infants, retention into PMTCT programs, the uptake of early infant diagnosis (EID) of HIV and infant HIV status. Risk ratios and random-effect meta-analysis were used in the analysis. RESULTS: Interventions assessed in the 34 identified studies included male partner involvement in PMTCT, peer mentoring, the use of community health workers (CHWs), mobile phone-based reminders, conditional cash transfer, training of midwives, integration of PMTCT services and enhanced referral. Five studies (two randomized) that evaluated mobile phone-based interventions showed a statistically significant increase (pooled RR 1.18; 95% CI 1.05 to 1.32, I(2)=83%) in uptake of EID of HIV at around six weeks postpartum. Male partner involvement in PMTCT was associated with reductions in infant HIV transmission (pooled RR 0.61; 95% CI 0.39 to 0.94, I(2)=0%) in four studies (one randomized). Four studies (three randomized) that were grounded on psychological interventions reported non-significant results (pooled RR 1.01; 95% CI 0.93 to 1.09, I(2)=69%) in increasing ARV/ART uptake among HIV-positive pregnant and/or breastfeeding women and infant HIV testing (pooled RR 1.00; 95% CI 0.94 to 1.07, I(2)=45%). The effect of the other interventions on the effectiveness of improving PMTCT uptake was unclear. Heterogeneity of interventions limits these findings. CONCLUSIONS: Our findings indicate that mobile phone-based reminders may increase the uptake of EID of HIV. Studies on male partner involvement in PMTCT reported reductions in infant HIV transmission. Stronger evidence is needed and future studies should determine the long-term effects of these interventions in improving retention throughout the PMTCT steps.

Verification of chemistry reference ranges using a simple method in sub-Saharan Africa.

BACKGROUND: Chemistry safety assessments are interpreted by using chemistry reference ranges (CRRs). Verification of CRRs is time consuming and often requires a statistical background. OBJECTIVES: We report on an easy and cost-saving method to verify CRRs. METHODS: Using a former method introduced by Sigma Diagnostics, three study sites in sub-Saharan Africa, Bondo, Kenya, and Pretoria and Bloemfontein, South Africa, verified the CRRs for hepatic and renal biochemistry assays performed during a clinical trial of HIV antiretroviral pre-exposure prophylaxis. The aspartate aminotransferase/alanine aminotransferase, creatinine and phosphorus results from 10 clinically-healthy participants at the screening visit were used. In the event the CRRs did not pass the verification, new CRRs had to be calculated based on 40 clinically-healthy participants. RESULTS: Within a few weeks, the study sites accomplished verification of the CRRs without additional costs. The aspartate aminotransferase reference ranges for the Bondo, Kenya site and the alanine aminotransferase reference ranges for the Pretoria, South Africa site required adjustment. The phosphorus CRR passed verification and the creatinine CRR required adjustment at every site. The newly-established CRR intervals were narrower than the CRRs used previously at these study sites due to decreases in the upper limits of the reference ranges. As a result, more toxicities were detected. CONCLUSION: To ensure the safety of clinical trial participants, verification of CRRs should be standard practice in clinical trials conducted in settings where the CRR has not been validated for the local population. This verification method is simple, inexpensive, and can be performed by any medical laboratory.

Pregnancy and contraceptive use among women participating in the FEM-PrEP trial.

BACKGROUND: Pregnancy among study participants remains a challenge for trials of new HIV prevention agents despite promotion and provision of contraception. We evaluated contraceptive use, pregnancy incidence, and study drug adherence by contraceptive method among women enrolled in the FEM-PrEP trial of once-daily oral tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for HIV prevention. METHODS: We required women to be using effective non-barrier contraception at enrollment. At each monthly follow-up visit, women were counseled on contraceptive use and tested for pregnancy. TDF-FTC adherence was determined by measuring plasma drug concentrations at 4-week intervals. We used Cox proportional hazards models to assess factors associated with incident pregnancy and multivariate logistic regression to examine the relationship between contraceptive method used at enrollment and TDF-FTC adherence. RESULTS: More than half of women were not using effective contraception before enrollment. Ninety-eight percent of these women adopted either injectable (55%) or oral (43%) contraceptives. The overall pregnancy rate was 9.6 per 100 woman-years. Among injectable users and new users of combined oral contraceptives (COCs), the rates were 1.6 and 35.1, respectively. New users of injectables had significantly greater odds of adhering to TDF-FTC than new COC users [odds ratio (95% confidence interval): 4.4 (1.7 to 11.6), P = 0.002], existing COC users [3.1 (1.3 to 7.3), P = 0.01], and existing injectable users [2.4 (1.1 to 5.6), P = 0.04]. CONCLUSIONS: Women using COCs during FEM-PrEP, particularly new adopters, were more likely to become pregnant and less likely to adhere to study product than injectable users. HIV prevention trials should consider requiring long-acting methods, including injectables, for study participation.

Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial.

BACKGROUND: Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensively among HIV-infected patients than among HIV-uninfected people. Using data from a pre-exposure trial - FEM-PrEP -, we determined the cumulative probabilities of grade 1+ ALT, AST and creatinine and grade 2+ phosphorus toxicities; ALT/AST toxicities by baseline hepatitis B status; and change in mean creatinine, phosphorus, ALT and AST levels controlling for TDF-FTC adherence. METHODS AND FINDINGS: FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among women in Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surface antigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatinine were measured regularly throughout the trial. TDF-FTC concentrations were measured to assess adherence to TDF-FTC. The cumulative probabilities of grade 1+ creatininemia and grade 2+ phosphatemia toxicities were not statistically different between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions of grade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surface antibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had higher mean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less than good adherence. CONCLUSIONS: We did not observe a significant relationship between randomization to TDF-FTC and creatinine or phosphorus toxicities. Women randomized to TDF-FTC had higher rates of mild to moderate ALT/AST toxicities, especially women with prior hepatitis B virus exposure. We also observed a significant increase in AST from baseline to week 4 among women who had higher adherence to TDF-FTC during that interval. TRIAL REGISTER: #NCT00625404, February 19, 2008.

Neurological syndrome in an HIV-prevention trial participant randomized to daily tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) in Bondo, Kenya.

Side effects of antiretroviral drug use by HIV-positive patients have been extensively studied; however, there are limited data on the side effects of antiretroviral drugs used as an HIV prophylaxis among healthy, HIV-negative individuals. Here we report on an unusual neuropathy in a 24-year-old participant in the FEM-PrEP trial. This was a Phase III randomized, double blind, placebo-controlled trial to test the safety and effectiveness of tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) (TDF-FTC) to prevent HIV. At the eighth week of taking TDF-FTC with moderate adherence, the participant complained of mild paresthesiae, numbness, and a tingling sensation in her upper limbs that was associated with pain and cold. After an additional 4 days, she developed a disabling weakness of her upper limbs and tremors in her hands. The study product was discontinued, and within 2 weeks she was free of all symptoms. One month after restarting the drug, she complained of posture-dependent numbness of her upper limbs. Results of clinical and neurological exams, laboratory tests, and magnetic resonance imaging are described here.

Analysis of HIV early infant diagnosis data to estimate rates of perinatal HIV transmission in Zambia.

BACKGROUND: Mother-to-child transmission of HIV (MTCT) remains the most prevalent source of pediatric HIV infection. Most PMTCT (prevention of mother-to-child transmission of HIV) programs have concentrated monitoring and evaluation efforts on process rather than on outcome indicators. In this paper, we review service data from 28,320 children born to HIV-positive mothers to estimate MTCT rates. METHOD: This study analyzed DNA PCR results and PMTCT data from perinatally exposed children zero to 12 months of age from five Zambian provinces between September 2007 and July 2010. RESULTS: The majority of children (58.6%) had a PCR test conducted between age six weeks and six months. Exclusive breastfeeding (56.8%) was the most frequent feeding method. An estimated 45.9% of mothers were below 30 years old and 93.3% had disclosed their HIV status. In terms of ARV regimen for PMTCT, 32.7% received AZT+single dose NVP (sdNVP), 30.9% received highly active antiretroviral treatment (HAART), 19.6% received sdNVP only and 12.9% received no ARVs. Transmission rates at six weeks when ARVs were received by both mother and baby, mother only, baby only, and none were 5.8%, 10.5%, 15.8% and 21.8% respectively. Transmission rates at six weeks where mother received HAART, AZT+sd NVP, sdNVP, and no intervention were 4.2%, 6.8%, 8.7% and 20.1% respectively. Based on adjusted analysis including ARV exposures and non ARV-related parameters, lower rates of positive PCR results were associated with 1) both mother and infant receiving prophylaxis, 2) children never breastfed and 3) mother being 30 years old or greater. Overall between September 2007 and July 2010, 12.2% of PCR results were HIV positive. Between September 2007 and January 2009, then between February 2009 and July 2010, proportions of positive PCR results were 15.1% and 11% respectively, a significant difference. CONCLUSION: The use of ARV drugs reduces vertical transmission of HIV in a program setting. Non-chemoprophylactic factors also play a significant role in HIV transmission. The overall change in the proportions of positive PCR results over time is more likely an indication of better PMTCT implementation. Determination of the outcomes of PMTCT in program settings is feasible but requires accurate documentation and analysis.