Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Slow and Steady But Not Related to HIV Stigma: Physical Activity in South Africans Living with HIV and Chronic Pain.

HIV stigma may influence physical activity in people living with HIV (PLWH) and chronic pain. We prospectively examined the relationship between stigma, activity and chronic pain in a convenience sample of PLWH initiating antiretroviral therapy in an inner-city clinic in Johannesburg, South Africa. Participants wore accelerometers to measure daily duration and intensity of activity for 2 weeks. Stigma was assessed with the Revised HIV Stigma Scale. Participants [n = 81, 89% female, age mean (SD) 42 (8)] were active for a median of 7 h daily (IQR 5.2, 9.2), but at very low intensity, equivalent to a slow walk [median (IQR): 0.39 m s-1 (0.33, 0.50)]. Duration and intensity of activity was not associated with stigma, even after controlling for age, self-assessed wealth, pain intensity and willingness to engage in physical activity (p-values > 0.05). As stigma did not associate with greater activity, drivers of sustained activity in South African PLWH remain unclear.

RESUMEN: El estigma del VIH puede influir en la actividad física de las personas que viven con el VIH (PVVS) y el dolor crónico. Se examinó prospectivamente la relación entre el estigma, la actividad y el dolor crónico en una muestra de conveniencia de PVVS que iniciaba la terapia antirretroviral en una clínica del centro de la ciudad en Johannesburgo, Sudáfrica. Los participantes usaron acelerómetros para medir la duración diaria y la intensidad de la actividad durante dos semanas. El estigma se evaluó con la escala revisada de estigma del VIH. Los participantes [n = 81, 89% mujeres, media de edad (SD) 42 (8)] tenían una actividad de intensidad muy baja, para una mediana de siete horas diarias (IQR 5.2, 9.2), pero, equivalente a una marcha lenta [mediana (IQR): 0.39 m s−1 (0.33, 0.50)]. La duración y la intensidad de la actividad no se asociaron con los niveles de estigma, incluso después de controlar la edad, la riqueza autoevaluada, la intensidad del dolor y la voluntad de participar en la actividad física (valores de p > 0.05). Como el estigma no se asoció con una mayor actividad, los impulsores de la actividad sostenida en las PVVS sudafricanas siguen sin estar claros.

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV.

BACKGROUND: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. METHODS: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTS: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONS: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.).

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

BACKGROUND: Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). METHODS: We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. RESULTS: There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. CONCLUSIONS: CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Participants on Dolutegravir Resuppress Human Immunodeficiency Virus RNA After Virologic Failure: Updated Data from the ADVANCE Trial.

Following evidence of HIV RNA re-suppression on DTG-based regimens, we assess the re-suppressive capacity of ADVANCE participants on TAF/FTC+DTG, TDF/FTC+DTG, and TDF/FTC/EFV. Viraemic participants were able to re-suppress within 3 follow-up visits of protocol-defined virological failure (PDVF) in 77/121 (64%), 85/126 (67%), and 44/138 (32%) cases respectively (DTG regimens vs. TDF/FTC/EFV; P < 0.001).

Virological suppression and clinical management in response to viremia in South African HIV treatment program: A multicenter cohort study.

BACKGROUND: Uptake of antiretroviral treatment (ART) is expanding rapidly in low- and middle-income countries (LMIC). Monitoring of virological suppression is recommended at 6 months of treatment and annually thereafter. In case of confirmed virological failure, a switch to second-line ART is indicated. There is a paucity of data on virological suppression and clinical management of patients experiencing viremia in clinical practice in LMIC. We report a large-scale multicenter assessment of virological suppression over time and management of viremia under programmatic conditions. METHODS AND FINDINGS: Linked medical record and laboratory source data from adult patients on first-line ART at 52 South African centers between 1 January 2007 and 1 May 2018 were studied. Virological suppression, switch to second-line ART, death, and loss to follow-up were analyzed. Multistate models and Cox proportional hazard models were used to assess suppression over time and predictors of treatment outcomes. A total of 104,719 patients were included. Patients were predominantly female (67.6%). Median age was 35.7 years (interquartile range [IQR]: 29.9-43.0). In on-treatment analysis, suppression below 1,000 copies/mL was 89.0% at month 12 and 90.4% at month 72. Suppression below 50 copies/mL was 73.1% at month 12 and 77.5% at month 72. Intention-to-treat suppression was 75.0% and 64.3% below 1,000 and 50 copies/mL at month 72, respectively. Viremia occurred in 19.8% (20,766/104,719) of patients during a median follow-up of 152 (IQR: 61-265) weeks. Being male and below 35 years of age and having a CD4 count below 200 cells/µL prior to start of ART were risk factors for viremia. After detection of viremia, confirmatory testing took 29 weeks (IQR: 16-54). Viral resuppression to below 1,000 copies/mL without switch of ART occurred frequently (45.6%; 6,030/13,210) but was associated with renewed viral rebound and switch. Of patients with confirmed failure who remained in care, only 41.5% (1,872/4,510) were switched. The median time to switch was 68 weeks (IQR: 35-127), resulting in 12,325 person-years spent with a viral load above 1,000 copies/mL. Limitations of this study include potential missing data, which is in part addressed by the use of cross-matched laboratory source data, and the possibility of unmeasured confounding. CONCLUSIONS: In this study, 90% virological suppression below the threshold of 1,000 copies/mL was observed in on-treatment analysis. However, this target was not met at the 50-copies/mL threshold or in intention-to-treat analysis. Clinical management in response to viremia was profoundly delayed, prolonging the duration of viremia and potential for transmission. Diagnostic tools to establish the cause of viremia are urgently needed to accelerate clinical decision-making.

Sex Differences in the Treatment of HIV.

PURPOSE OF REVIEW: Biological and societal influences are different for men and women leading to different HIV outcomes and related infectious and non-infectious complications. This review evaluates sex differences in the epidemiology and immunological response to HIV and looks at major complications and coinfections, as well as care delivery systems focusing on low- and middle-income countries (LMICs) where most people with HIV live. RECENT FINDINGS: More women than men access testing and treatment services in LMIC; women are more likely to be virologically suppressed in that environment. There is a growing recognition that the enhanced immunological response to several pathogens including HIV may result in improved outcomes for infectious comorbidities but may result in a greater burden of non-communicable diseases. Men and women have different requirements for HIV care. Attention to these differences may improve outcomes for all.

Cardiovascular disease risk in an urban African population: a cross-sectional analysis on the role of HIV and antiretroviral treatment.

BACKGROUND: Life expectancy is increasing in the HIV-positive population and age-related non-communicable diseases, such as cardiovascular disease, (CVD) are seen more frequently. This study investigated to what extent HIV and antiretroviral therapy (ART) is associated with CVD risk in an urban African population. METHODS: A cross-sectional study was performed in Johannesburg, South Africa, between July 2016 and November 2017. Both HIV-positive adults (ART-naïve, or on first- or second-line ART), as well as age and sex matched HIV-negative controls who were family or friends of the HIV-positive participants were included. Data were collected on demographics, cardiovascular risk factors, HIV-related characteristics, carotid intima-media thickness (CIMT) and carotid distensibility. The association between HIV, ART and CIMT and distensibility was analysed with linear regression models, adjusting for age, gender and CVD risk factors. RESULTS: The study included 548 participants, 337 (62%) females, age 38.3 ± 9.5 years of whom 104 (19.0%) were HIV-positive, ART-naïve; 94 (17.2%) were on first-line ART; 197 (35.9%) were on second-line ART; and 153 (27.9%) were HIV-negative. Participants on second-line ART had higher CIMT and lower distensibility compared to the other groups (p < 0.001). After adjustment for age, these outcomes were similar between groups. Further adjustment for CVD and HIV-related factors did not alter the findings. CONCLUSION: Neither HIV nor ART was associated with CIMT or carotid distensibility in this urban African population. Longitudinal studies are needed to fully understand the relationship between HIV and CVD across different populations.

Lipid levels, insulin resistance and cardiovascular risk over 96 weeks of antiretroviral therapy: a randomised controlled trial comparing low-dose stavudine and tenofovir.

BACKGROUND: HIV infection and antiretroviral treatment are associated with changes in lipid levels, insulin resistance and risk of cardiovascular disease (CVD). We investigated these changes in the first 96 weeks of treatment with low-dose stavudine or tenofovir regimens. METHODS: This is a secondary analysis of a double blind, randomised controlled trial performed in South-Africa, Uganda and India comparing low-dose stavudine (20 mg twice daily) with tenofovir in combination with efavirenz and lamivudine in antiretroviral-naïve adults (n = 1067) (Clinicaltrials.gov, NCT02670772). Over 96 weeks, data were collected on fasting lipids, glucose and insulin. Insulin resistance was assessed with the HOMA-IR index and 10-year CVD risk with the Framingham risk score (FRS). A generalized linear mixed model was used to estimate trends over time. RESULTS: Participants were on average 35.3 years old, 57.6% female and 91.8% Black African. All lipid levels increased following treatment initiation, with the sharpest increase in the first 24 weeks of treatment. The increase in all lipid subcomponents over 96 weeks was higher among those in the stavudine than the tenofovir group. Insulin resistance increased steadily with no difference detected between study groups. FRS rose from 1.90% (1.84-1.98%) at baseline to 2.06 (1.98-2.15%) at week 96 for the total group, with no difference between treatment arms (p = 0.144). Lipid changes were more marked in Indian than African participants. CONCLUSION: Lipid levels increased in both groups, with low-dose stavudine resulting in a worse lipid profile compared to tenofovir. Insulin resistance increased, with no difference between regimens. CVD risk increased over time and tended to increase more in the group on stavudine. The low CVD risk across both arms argues against routine lipid and glucose monitoring in the absence of other CVD risk factors. In high risk patients, monitoring may only be appropriate at least a year after treatment initiation.

HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project.

BACKGROUND: Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. METHODS AND FINDINGS: The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. CONCLUSIONS: PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa.

Is laboratory screening prior to antiretroviral treatment useful in Johannesburg, South Africa? Baseline findings of a clinical trial.

BACKGROUND: Screening for renal, hepatic and haematological disorders complicates the initiation of current first-line antiretroviral therapy (ART). Each additional test done adds substantial costs, both through direct laboratory expenses, but also by increasing the burden on health workers and patients. Evaluating the prevalence of clinically relevant abnormalities in different population groups could guide decisions about what tests to recommend in national guidelines, or in local adaptations of these. METHODS: As part of enrolment procedures in a clinical trial, 771 HIV-positive adults, predominantly from inner-city primary health care clinics, underwent laboratory screening prior to ART. Participants had to be eligible for ART, based on the then CD4 eligibility threshold of 350 cells/µL, antiretroviral naïve and have no symptoms of peripheral neuropathy. RESULTS: Participants were mostly female (57%) and a mean 34 years old. Creatinine clearance rates were almost all above 50 mL/min (99%), although 5% had microalbuminuria. Hepatitis B antigenaemia was common (8% of participants), of whom 40% had a raised AST/ALT, though only 2 had transaminase levels above 200 IU/L. Only 2% of participants had severe anaemia (haemoglobin <8 g/dl) and 1% neutropaenia (neutrophils <0.75 × 10^9/L). Costs per case detected of hepatitis B infection was USD135, but more than USD800 for a raised creatinine. CONCLUSIONS: Hepatitis B continues to be a common co-infection in HIV-infected adults, and adds complexity to management of ART switches involving tenofovir. Routine renal and haematological screening prior to ART detected few abnormalities. The use of these screening tests should be assessed among patients with higher CD4 counts, who may even have fewer abnormalities. Formal evaluation of cost-effectiveness of laboratory screening prior to ART is warranted.

Final 192-Week Efficacy and Safety Results of the ADVANCE Trial, Comparing 3 First-line Antiretroviral Regimens.

Background: ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive. Methods: This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks. Results: Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm. Conclusions: High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes.

Is there a role for doravirine in African HIV treatment programmes? A large observational resistance study in South Africa.

INTRODUCTION: Dolutegravir has replaced efavirenz in most low- and middle-income countries, due to better tolerability and formidable resistance profile, but dolutegravir side effects suggest alternatives are needed. We evaluated doravirine resistance in South Africa as a first step to assess whether doravirine may replace dolutegravir. METHODS: A retrospective dataset was analysed for predicted doravirine susceptibility, including sequences obtained from three patient groups. First, data from 277 patients initiating antiretroviral treatment (ART) were collected between February 2013 and October 2014 as part of a national survey. Second, data from 788 patients experiencing NNRTI-based ART failure were obtained between February 2013 and October 2014 as part of a national survey. Third, data derived from 584 patients who had genotypic drug resistance testing requested after NNRT-based failure as part of individual patient management between January 2016 and December 2019. Pol sequences were generated using validated population-based in-house genotyping and submitted to Stanford HIVdb v8.9. RESULTS AND DISCUSSION: Less than 5% of patients initiating ART presented with genotypic doravirine resistance, whereas most patients experiencing NNRTI-based ART failure presented with predicted intermediate (41.0%) or high-level resistance (43.8%) to doravirine. High-level resistance to doravirine was commonly predicted by the presence of at least three DRMs (79.7%). The predicted resistance profile to doravirine in ART-naïve patients is promising, but less so in those experiencing failure to first-generation NNRTIs. Accumulation of NNRTI DRMs seems to be an important factor in the poor resistance prediction for doravirine. CONCLUSIONS: Although doravirine is approved as initial therapy in patients who are ART-naïve, it is currently recommended to obtain a genotype prior to the initiation of ART. Clinical studies are needed to ascertain whether predicted resistance profiles in ART naïve and NNRTI-treated patients translate into poor clinical outcomes, especially in settings where genotypic resistance testing is not available.

High individual pain variability in people living with HIV: A graphical analysis.

BACKGROUND: People living with HIV (PLWH) frequently experience pain. Following calls to analyse individual-level data in addition to group-level data in pain studies, we compared individual and group-level changes in pain prevalence, intensity and number of pain sites over 48 weeks in a large cohort of PLWH. This is the largest ever cohort study of pain in PLWH, and is the first to report pain at the level of the individual. METHODS: Participants included all participants with complete pain records from a randomized clinical trial (RCT) for the treatment of HIV (n = 787/1053). At weeks 0, 12, 24, 36 and 48 we assessed participants' pain in the last week; presence of pain, and if present, the intensity and locations of the pain. We used standard averaging methods to describe data at the group level, and unique graphical reporting methods to analyse data at the level of the individual. RESULTS: Group-level data demonstrated a trend for pain prevalence to decline over time (19% week 0, 12% week 48). Worst pain intensity remained stable (median between 4/10 and 5/10), as did the number (median = 1) and common sites of pain across the 48 weeks. In contrast, individual-level data demonstrated high intra-individual variability with regards to the presence of pain, and the intensity and location of the pain. CONCLUSIONS: While our group-level data were similar to previous longitudinal studies, an apparent reduction in pain over 48 weeks, the individual-level data showed large variability within individuals in that same time frame. SIGNIFICANCE: This graphical analysis highlights the high variability in pain (pain prevalence, intensity and body sites) across time in people living with HIV, and how presenting averaged data hides this important variability. Our data support the reporting of individual-level data in human experimental and observational studies.

Gastrointestinal manifestations of human immunodeficiency virus and coronavirus disease 2019: Understanding the intersecting regions between the two epidemics.

In March 2020, the World Health Organization declared coronavirus disease (COVID-19) a pandemic. As of February 2021, there were 107 million COVID-19 cases worldwide. As a comparison, there are approximately 38 million people living with human immunodeficiency virus (PLHIV) worldwide. The coexistence of both epidemics, and the syndemic effect of both viruses could lead to a delirious impact both at individual and community levels. Many intersecting points were found between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, and HIV; among which, gastrointestinal (GI) manifestations are the most notable. GI manifestations represent a common clinical presentation in both HIV and SARS-CoV-2. The emergence of GI symptoms as a result of SARS-CoV-2 infection provides a new dynamic to COVID-19 diagnosis, management, and infection control measures, and adds an additional diagnostic challenge in case of coinfection with HIV. The presence of GI manifestations in PLHIV during the COVID-19 pandemic could be referred to HIV enteropathy, presence of opportunistic infection, adverse effect of antiretrovirals, or coinfection with COVID-19. Thus, it is important to exclude SARS-CoV-2 in patients who present with new-onset GI manifestations, especially in PLHIV, to avoid the risk of disease transmission during endoscopic interventions. Structural similarities between both viruses adds a valuable intersecting point, which has mutual benefits in the management of both viruses. These similarities led to the hypothesis that antiretrovirals such as lopinavir/Rironavir have a role in the management of COVID-19, which was the target of our search strategy using the available evidence. These similarities may also facilitate the development of an efficient HIV vaccine in the future using the advances in COVID-19 vaccine development.

Corrigendum: Southern African guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020.

[This corrects the article DOI: 10.4102/sajhivmed.v21i1.1152.].

Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.

OBJECTIVE: Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir. DESIGN: We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial. METHODS: We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir-alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir-disoproxil-fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV). RESULTS: Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/µl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ±â€Š8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (-1.8 ±â€Š8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (-5.9 ±â€Š8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ±â€Š7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ±â€Š8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by -3.3 ±â€Š8.1 with TDF/FTC/EFV arm. CONCLUSION: Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.

Phase 3 trials of new antiretrovirals are not representative of the global HIV epidemic.

INTRODUCTION: People living with HIV (PLWH) are mainly African or Asian, the majority female. In contrast, pharmaceutical companies typically conduct phase 3 regulatory randomised controlled trials (RCTs) in high-income countries (HICs), where PLWH are mainly white males. Regulatory authorities can be conservative about including pregnant women in trials, discouraging female participation. Some adverse events occur more frequently by sex or by race because of differing pharmacokinetics. Most drugs have insufficient safety data in pregnancy and non-white people even after regulatory approval. The present study compared race and sex demographics of phase 3 RCTs of dolutegravir (DTG), bictegravir (BIC) and tenofovir alafenamide (TAF) with global HIV epidemic demography. METHODS: National epidemic sizes by sex were extracted from UNAIDS 2018 data. National demographics were used to estimate prevalence by race. PLWH by national socio-economic status were calculated from World Bank data. Summary race and sex demographic data for 10 phase 3 trials of DTG (n = 7714), four of BIC (n = 2307), eight of TAF (n = 7573) and two of doravirine (DOR) (n = 1407) were extracted from ClinicalTrials.gov. RESULTS: Black females (42%) and black males (30%) have highest prevalence globally. White males comprise 6% of PLWH. Over 60% of PLWH live in low or low-middle-income countries, 68% of whom are black and 23% Asian. Seventy-six per cent of DTG trial centres were in high-income countries (HICs) (5% global burden) and 23% in upper-middle-income countries (UMICs). DTG trials were not representative of PLWH even within the UMIC and HIC setting (49% white male vs 31% income band). White males were overrecruited by 44% to DTG, BIC, TAF and DOR trials in comparison with prevalence. Black females were underrepresented by 35%. CONCLUSION: Phase 3 RCT populations for new antiretrovirals comprised 51% white males, vastly disproportionate to the global HIV epidemic (6%). Females and non-white people are underrepresented. Female safety data are insufficient despite drug approval in Europe and USA. HIV trials should be located in regions representing the global epidemic with no sex-based selection. Trials should aim for at least 50% female and 50% non-white recruitment to properly provide safety information.

Time to rethink endpoints for new clinical trials of antiretrovirals? Long-term re-suppression of HIV RNA with integrase inhibitors.

: In the ADVANCE study of first-line treatment, there were 48 participants with HIV RNA at least 50 copies/ml in the week 48 window who had subsequent follow-up data available with no change in randomized treatment. More participants achieved virological re-suppression in the TAF/FTC+DTG and TDF/FTC+DTG arms (26/34, 76%) than on TDF/FTC/EFV (6/14 = 43%; P = 0.0421). It is unclear whether participants with HIV RNA at least 50 copies/ml at week 48 should be termed 'virological failures' on integrase inhibitor-based treatment.