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Background: In South Africa, women continue to face a high burden of Human Immunodeficiency Virus (HIV) infection and the possible complications thereof during pregnancy. We assessed pregnancy incidence rates and outcomes in a longitudinal HIV cohort study over a 15-year period. Methods: We evaluated pregnancies among women ≥ 18 years between 2004 and 2019 in the CAPRISA 002 study. We analysed pregnancy rates following HIV acquisition, CD4 counts and HIV viral load dynamics and pregnancy outcomes. We used linear regression to assess if the mean CD4 and log10 viral load close to delivery increases or decreases linearly across three different timepoints. Results: In total 245 women enrolled into the HIV negative study phase, 225 into the HIV infection phase and 232 in the antiretroviral therapy (ART) phase. Median follow-up time was 2.0 years [Interquartile Range (IQR) 0.8–2.0] during the HIV negative phase, 2.6 years; (IQR) 1.2–4.8] during HIV infection and 3.7 years (IQR 1.8–5.0) on ART, with maximum follow-up time of 2, 10 and 6 years respectively. Overall, 169 pregnancies occurred in 140 women, of which 16 pregnancies were observed during acute or early HIV infection [Incidence Rate (IR) 8.0 per 100 women-years; 95% confidence interval (CI): 4.6—12.9], 48 during established infection [IR 9.3; (CI 6.8–12.3)] and 68 on ART [IR 8.9; (CI: 7.0 – 11.4)]. Birth outcomes from 155/169 (91.7%) pregnancies were 118 (76.1%) full term live births, 17 (10.9%) premature live births, 9 (5.8%) therapeutic/elective miscarriages, 8 (5.1%) spontaneous miscarriages and 3 (1.9%) spontaneous foetal deaths or stillbirths. Six mother-to-child transmission events occurred, with four documented prior to 2008. Over time, mean CD4 count in pregnant women increased from 395 cells/µL (2004—2009) to 543 cells/µL (2010–2014) and to 696 cells/µL (2015–2019), p < 0.001. Conversely, the viral load declined from 4.2 log10 copies/ml to 2.5 log10 copies/ml and to 1.2 log10 copies/ml (p < 0.001) for the corresponding periods. Conclusions: Pregnancy rates following HIV acquisition were high, emphasising a need for timeous ART provision and contraception counselling in women recently diagnosed with HIV. CD4 count and HIV viral load trajectories reflect improvements in treatment guidance for pregnant women over time. [ABSTRACT FROM AUTHOR]

Background New onset or worsening drug-induced liver injury challenges coinfected patients on antiretroviral therapy (ART) initiation during antituberculosis (TB) treatment. Methods Post hoc analysis within a randomized trial, the Starting Antiretroviral Therapy at Three Points in Tuberculosis trial, was conducted. Patients were randomized to initiate ART either early or late during TB treatment or after TB treatment completion. Liver enzymes were measured at baseline, 6-month intervals, and when clinically indicated. Results Among 642 patients enrolled, the median age was 34 years (standard deviation, 28–40), and 17.6% had baseline CD4+ cell counts <50 cells/mm3. Overall, 146/472 patients (52, 47, and 47: early, late, and sequential arms) developed new-onset liver injury following TB treatment initiation. The incidence of liver injury post-ART initiation in patients with CD4+ cell counts <200 cells/mm3 and ≥200 cells/ mm3 was 27.4 (95% confidence interval [CI], 18.0–39.8), 19.0 (95% CI, 10.9–30.9), and 18.4 (95% CI, 8.8–33.8) per 100 person-years, and 32.1 (95% CI, 20.1–48.5), 11.8 (95% CI, 4.3–25.7), and 28.2 (95% CI, 13.5–51.9) per 100 person-years in the early, late integrated, and sequential treatment arms, respectively. Severe and life-threatening liver injury occurred in 2, 7, and 3 early, late, and sequential treatment arm patients, respectively. Older age and hepatitis B positivity predicted liver injury. Conclusions High incidence rates of liver injury among cotreated human immunodeficiency virus (HIV)–TB coinfected patients were observed. Clinical guidelines and policies must provide guidance on frequency of liver function monitoring for HIV–TB coinfected patients. [ABSTRACT FROM AUTHOR]

Background: A large and compelling clinical evidence base has shown that integrated TB and HIV services leads to reduction in human immunodeficiency virus (HIV)- and tuberculosis (TB)-associated mortality and morbidity. Despite official policies and guidelines recommending TB and HIV care integration, its poor implementation has resulted in TB and HIV remaining the commonest causes of death in several countries in sub-Saharan Africa, including South Africa. This study aims to reduce mortality due to TB-HIV co-infection through a quality improvement strategy for scaling up of TB and HIV treatment integration in rural primary healthcare clinics in South Africa.Methods: The study is designed as an open-label cluster randomized controlled trial. Sixteen clinic supervisors who oversee 40 primary health care (PHC) clinics in two rural districts of KwaZulu-Natal, South Africa will be randomized to either the control group (provision of standard government guidance for TB-HIV integration) or the intervention group (provision of standard government guidance with active enhancement of TB-HIV care integration through a quality improvement approach). The primary outcome is all-cause mortality among TB-HIV patients. Secondary outcomes include time to antiretroviral therapy (ART) initiation among TB-HIV co-infected patients, as well as TB and HIV treatment outcomes at 12 months. In addition, factors that may affect the intervention, such as conditions in the clinic and staff availability, will be closely monitored and documented.Discussion: This study has the potential to address the gap between the establishment of TB-HIV care integration policies and guidelines and their implementation in the provision of integrated care in PHC clinics. If successful, an evidence-based intervention comprising change ideas, tools, and approaches for quality improvement could inform the future rapid scale up, implementation, and sustainability of improved TB-HIV integration across sub-Sahara Africa and other resource-constrained settings.Trial Registration: Clinicaltrials.gov, NCT02654613 . Registered 01 June 2015. [ABSTRACT FROM AUTHOR]

The article offers information on the effect of universal testing and treatment on community human immunodeficiency virus (HIV) incidence. It mentions three trials of universal testing and treatment show varying outcomes, from modest to no reductions in HIV incidence; and also mentions three and a half of the four trials of universal testing and treatment did not show significant reductions in HIV incidence.

The CAPRISA 004 preexposure prophylaxis (PrEP) randomized trial demonstrated that women who used a vaginal gel containing the antiretroviral drug tenofovir (TFV) had a 39% lower risk of acquiring human immunodeficiency virus (HIV). It is not known whether topical TFV alters the antibody response to breakthrough HIV infection. In this study, antibody maturation was evaluated using 3 serologic assays: the BED capture enzyme immunoassay (CEIA), the Bio-Plex (Luminex) assay, and the Bio-Rad avidity assay. Tests were performed using serum samples collected 3, 6, 9, 12, 24, 36, 48, and >48 months after seroconversion from 95 women in the CAPRISA 004 trial (35 in the TFV gel arm and 60 in the placebo arm). For the BED CEIA and Luminex assay, linear mixed effects models were used to examine test results by study arm. Cox proportional hazard analysis was used to examine time to avidity cutoff. Anti-HIV antibody titers did not differ between study arms. Women assigned to TFV gel demonstrated slower antibody avidity maturation, as determined by the Bio-Rad (P = .04) and gp120 Bio-Plex (P = .028) assays. Women who were assigned to receive topical TFV but became infected had slower antibody avidity maturation, with potential implications for diagnosis and antibody-based incidence assays as access to antiretroviral therapy-based PrEP is increased. [ABSTRACT FROM AUTHOR]

This study shows that one-third of HIV subtype C–infected women require antiretroviral therapy within 12 months of infection, increasing to 69% if the initiation CD4 count is 500 cells/µL. This has significant implications for program implementation, resource allocation, and HIV prevention.Background. Whereas human immunodeficiency virus (HIV) subtype B–infected individuals generally progress to AIDS within 8–10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C–infected South African women.Methods. Prospective seroincidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n = 245) or every 3 months (n = 594) for up to 4 years. Rapid disease progression was defined as CD4 decline to <350 cells/µL by 2 years postinfection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models.Results. Sixty-two women were identified at a median of 42 days postinfection (interquartile range, 34–59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months postinfection in women with preinfection measurements. CD4 decline to <350 cells/µL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years postinfection, respectively, and to <500 cells/µL in 69%, 79%, and 81% at equivalent timepoints. Predictors of rapid progression were CD4 count at 3 months postinfection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31–3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51–9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31–15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non–rapid progression (HR, 0.19; 95% CI, .05–.74; P = .016).Conclusions. Nearly half of subtype C–infected women progressed to a CD4 count <350 cells/µL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4 count <500 cells/µL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection. [ABSTRACT FROM AUTHOR]

Background: We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods: We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results: At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). Conclusions: Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.) [ABSTRACT FROM PUBLISHER]

The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use. [ABSTRACT FROM AUTHOR]

The article presents a clinical assessment on the effectiveness of topical and oral antiretroviral pre-exposure prophylaxis (PrEP) in treating women with HIV in sub-Saharan Africa. The low pill adherence and inadequate drug concentrations at the site infection explains the inability of oral tenofovir disoproxil fumarate and emtricitabine to prevent women's HIV. The oral dosing of drugs has been observed for its lower drug concentration than the topical application of tenofovir gel.

In this article, the author discusses the denial and unawareness expressed by people who are exposed to HIV/AIDS virus in South Africa. According to him, the associated stigma brought by the infection hinders AIDS prevention and treatment, while Africans who volunteer for HIV tests are less. He also highlights the inadequacy of utilizing antiretroviral drugs and disease education for successful AIDS control and suggests behavior modification and fear recognition.

Intermittent use of a single antiretroviral agent in the presence of a replicating virus could potentially increase the development of antiviral resistance. The pericoital, before-and-after sex, dosing regimen used in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial meant that women who were infected with hepatitis B virus (HBV) were exposed intermittently to tenofovir during their participation. The impact of this dosing regimen on HBV resistance was assessed by amplification of the HBV polymerase region from 37 stored plasma samples of women who were HBV surface antigen positive. All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important. [ABSTRACT FROM AUTHOR]

Introduction: Young women in sub‐Saharan Africa are disproportionately affected by HIV, accounting for 25% of all new infections in 2017. Several behavioural and biological factors are known to impact a young woman's vulnerability for acquiring HIV. One key, but lesser understood, biological factor impacting vulnerability is the vaginal microbiome. This review describes the vaginal microbiome and examines its alterations, its influence on HIV acquisition as well as the efficacy of HIV prevention technologies, the role of the rectal microbiome in HIV acquisition, advances in technologies to study the microbiome and some future research directions. Discussion: Although the composition of each woman's vaginal microbiome is unique, a microbiome dominated by Lactobacillus species is generally associated with a "healthy" vagina. Disturbances in the vaginal microbiota, characterized by a shift from a low‐diversity, Lactobacillus‐dominant state to a high‐diversity non‐Lactobacillus‐dominant state, have been shown to be associated with a range of adverse reproductive health outcomes, including increasing the risk of genital inflammation and HIV acquisition. Gardnerella vaginalis and Prevotella bivia have been shown to contribute to both HIV risk and genital inflammation. In addition to impacting HIV risk, the composition of the vaginal microbiome affects the vaginal concentrations of some antiretroviral drugs, particularly those administered intravaginally, and thereby their efficacy as pre‐exposure prophylaxis (PrEP) for HIV prevention. Although the role of rectal microbiota in HIV acquisition in women is less well understood, the composition of this compartment's microbiome, particularly the presence of species of bacteria from the Prevotellaceae family likely contribute to HIV acquisition. Advances in technologies have facilitated the study of the genital microbiome's structure and function. While next‐generation sequencing advanced knowledge of the diversity and complexity of the vaginal microbiome, the emerging field of metaproteomics, which provides important information on vaginal bacterial community structure, diversity and function, is further shedding light on functionality of the vaginal microbiome and its relationship with bacterial vaginosis (BV), as well as antiretroviral PrEP efficacy. Conclusions: A better understanding of the composition, structure and function of the microbiome is needed to identify opportunities to alter the vaginal microbiome and prevent BV and reduce the risk of HIV acquisition. [ABSTRACT FROM AUTHOR]

The author reflects on the global implementation of early antiretroviral therapy (ART) to address the human immunodeficiency virus (HIV) epidemic as of August 2015. He cites the long-standing debate on when to start ART in asymptomatic persons, and the viral suppression rates exceeding 95% and 85% of patients initiating ART early in the START and TEMPRANO trials, respectively. The author states that converting these trials into treatment programs will need substantial additional resources.

An editorial is presented on the decline in efforts to eliminate HIV. It states that nearly 30 new antiretroviral drugs that are inexpensive, have minimal side effects, and only need be taken once a day have allowed HIV-positive people to live a nearly normal life span. It mentions that despite beliefs the AIDS epidemic is over, nearly 5,000 new cases of HIV infection occur daily and talks about the stigma that HIV-positive people have to live with.

The article presents a review on the preventive strategies for HIV in the U.S. It provides an analysis on the effectiveness of implementing the combined prevention strategies to be able to reduce the HIV pandemic. It highlights the review on the developments in HIV prevention such as the knowledge gap of the disease, the discovery for new vaccines, and the challenges related to the antiretroviral-based prevention.

Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4+ T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4+ T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4+ T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4+ T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis-speciftc CD4+ T cells showed little change, whereas CMV-specific CD4+ T cells were significantly lower (p = 0.003). There was no difference in the polvfunctional or memory profile of Ag-specific CD4+ T cells before and after ART. The replenishment of Ag-specific CD4+ T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4+ T cells exhibiting a late differentiated profile (CD45RO+CD27-) had a lower capacity to replenish (p = 0.019; r = - 0 . 5) compared with cells with an early differentiated profile (CD45RO+CD27+; p = 0.04; r = 0.45). In conclusion, restoration of copathogen-specific memory CD4+ T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberai- /osís-specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIVinfected individuals on ART. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. Methodology: Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated. Results: In 57 patients, median (IQR) C2.5hr was 3.6 (2.8-5.0) ng/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low median rifampicin C2 .5hr, 3.7 (2.8-5.0) ng/inL in the heterozygous and 3.4 (2.7-4.7) ng/inL in the homozygous variant carriers. Concentrations were also low in males (p < 0.0001) and those with low haemoglobin (p = 0.02). Although reinfection could not be distinguished from reactivation for the 43 patients followed post trial, the incidence of TB recurrence was 7.1 per 100 person-years. Of the eight patients in whom TB recurred, seven had the polymorphism. Conclusion: Approximated peak rifampicin concentrations were well below the recommended target range of 8 to 24 |xg/mL in this patient population with its high frequency of the SLCO1B1 (rs4149032) polymorphism. Increased rifampicin dosage may be warranted in African, HIV- TB co-infected patients. [ABSTRACT FROM AUTHOR]