Clinical Outcomes in a Randomized Controlled Trial Comparing Point-of-Care With Standard Human Immunodeficiency Virus (HIV) Viral Load Monitoring in Nigeria.

BACKGROUND: Point-of-care (POC) viral load (VL) tests provide results within hours, enabling same-day treatment interventions. We assessed treatment outcomes with POC vs standard-of-care (SOC) VL monitoring. METHODS: We implemented a randomized controlled trial at an urban and rural hospital in Nigeria. Participants initiating antiretroviral therapy (ART) were randomized 1:1 for monitoring via the POC Cepheid Xpert or SOC Roche COBAS (v2.0) HIV-1 VL assays. Viral suppression (VS) and retention in care at 12 months were compared via intention-to-treat (ITT) and per-protocol (PP) analyses. Post-trial surveys for POC patients and healthcare workers (HCWs) evaluated acceptability. RESULTS: During April 2018-October 2019, 268 SOC and 273 POC patients enrolled in the trial. Viral suppression at <1000 copies/mL at 12 months was 59.3% (162/273) for POC and 52.2% (140/268) for SOC (P = .096) in ITT analysis and 77.1% (158/205) for POC and 65.9% (137/208) for SOC (P = .012) in PP analysis. Retention was not significantly different in ITT analysis but was 85.9% for POC and 76.9% for SOC (P = .02) in PP analysis. The increased VS in the POC arm was attributable to improved retention and documentation of VL results. POC monitoring was preferred over SOC by 90.2% (147/163) of patients and 100% (15/15) of HCWs thought it facilitated patient care. CONCLUSIONS: POC VL monitoring did not improve 12-month VS among those with results but did improve retention and VS documentation and was preferred by most patients and HCWs. Further research can inform best POC implementation conditions and approaches to optimize patient care. CLINICAL TRIALS REGISTRATION: NCT03533868.

Timeliness of Point-of-Care Viral Load Results Improves Human Immunodeficiency Virus Monitoring in Nigeria.

BACKGROUND: Human immunodeficiency virus (HIV) viral load (VL) monitoring is critical for antiretroviral therapy (ART) management. Point-of-care (POC) VL testing has been reported to be feasible and preferred over standard-of-care (SOC) testing in many low- and middle-income country settings where rapid results could improve patient outcomes. METHODS: The timeliness of receipt of VL results was evaluated in an open-label, randomized, controlled trial among patients newly initiating ART. Clinical outcomes with POC VL monitoring using Cepheid Xpert vs SOC VL at Jos University Teaching Hospital and Comprehensive Health Centre Zamko in Nigeria were assessed. We determined time between specimen collection and recording of VL in patient charts, receipt of results, and ART switch for those who met virologic failure criteria. RESULTS: Between April 2018 and October 2019, we screened 696 ART-naive individuals; 273 were randomized to POC and 268 to SOC HIV-1 VL testing. Participants in the POC arm received VL results significantly faster than those in the SOC arm (0.1 median days, interquartile range [IQR], 0.1-0.2 vs 143.1 days, IQR, 56.0-177.1, respectively; P < .0001). Participants in the POC arm with confirmed virologic failure vs those in the SOC arm were switched more rapidly to a second-line regimen (0 median days, IQR, 0-28 vs 66 days, IQR, 63-123, respectively; P = .03). CONCLUSIONS: POC VL testing resulted in significant improvement in the timeliness of VL result receipt by patients and use for effective HIV clinical management. In patients experiencing VL failure, POC monitoring enabled prompt switching to second-line ART regimens. CLINICAL TRIALS REGISTRATION: NCT03533868.

Achieving a robust mentoring and research capacity program in a LMIC - the BRAINS faculty development model.

BACKGROUND: A research and training program (RTP) was carried out to build the capacity of faculty and improve the culture of research in the College of Medicine, University of Lagos (CMUL), Nigeria. METHODS: Realist-guided mixed methods evaluation of the BRAINS project was carried out using secondary data generated during the 5-years (2015 - 2020) of project implementation. Capacity building workshops and mentored research activities targeted at faculty in the CMUL were conducted. Overall, 1,418 participants attended the workshops in batches. Among the participants, forty-five faculty received grants and were mentored by senior professionals (local & international) to conduct research. Data were extracted from all project-related documents including coursework biodata, workshop evaluation forms, quarterly project reports, and end- of-project reports, submitted by the mentees, minutes of meetings, and the proposal submitted for funding. It was in the form of continuous variables and prose (sentences & stories). Quantitative data were analysed with IBM SPSS statistics version 20. Mean knowledge score and mean difference was calculated, paired t-test was carried out using p < 0.05 to determine statistical significance. The prose was thematically analysed to generate themes and narratives. Both were subsequently combined for interpretation and used to refine the initial programme theory into an evidence-informed theory. RESULTS: Twelve courses were deployed, and 1,418 participants (47.8% males and 52.2% females) from medical, nursing, and allied medical departments were trained. Eighty participants were trained in Responsible Conduct of Research and eighty-one on Manuscript Writing over three years. A comparison of the pre/post-test knowledge scores showed a positive mean difference. Thematic analysis of workshop data produced three thematic domains representing effectiveness and gains namely: cognitive, reward, and behavioural. 45 trainees were awarded grants and mentored, and analysis of mentee's data generated 4 themes: Achieving a robust mentoring program; Benefits of the mentoring program; Resilience in research; Improving the mentoring program. CONCLUSION: By contributing to the body of knowledge available on RTPs, this evaluation identified key components that contributed to the success of the project and developed a model for achieving a robust training and mentoring program which can be replicated in other LMICs.

Acceptability of and Preferences for Long-Acting Injectable HIV PrEP and Other PrEP Modalities among Sexual Minority Men in Nigeria, Africa.

Sexual minority men (SMM) in Nigeria have been disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) reduces risk for HIV acquisition among SMM by over 90%. The current study investigated the association between demographics, socioeconomic marginalization, sexual health and willingness to use long-acting injectable (LAI-) PrEP and preferences for other PrEP modalities in a sample of HIV-negative SMM in Nigeria. Between March and June 2019, SMM residing in Abuja, Delta, Lagos, and Plateau completed a quantitative survey. To examine willingness to use LAI-PrEP and PrEP modality preferences, multivariable binomial and multinomial logistic regression models were fit. We found that 88% were willing to use LAI-PrEP and 44% preferred LAI-PrEP to other PrEP modalities. Participants who reported interest in LAI-PrEP were more likely to be single, engage in inconsistent condom use, and report having a primary care provider. Compared to participants who preferred daily oral PrEP, participants who preferred other PrEP modalities had higher odds of having some university education/university degree or higher and reporting low financial hardship. It is imperative that SMM in Nigeria are prioritized for access to new HIV prevention interventions, as they bear a disproportionate burden of HIV and are especially vulnerable to HIV infection.

In well-differentiated primary human bronchial epithelial cells, TGF-ß1 and TGF-ß2 induce expression of furin.

The COVID-19 pandemic is an ongoing threat to public health. Since the identification of COVID-19, the disease caused by SARS-CoV-2, no drugs have been developed to specifically target SARS-CoV-2. To develop effective and safe treatment options, a better understanding of cellular mechanisms underlying SARS-CoV-2 infection is required. To fill this knowledge gap, researchers require reliable experimental systems that express the host factor proteins necessary for the cellular entry of SARS-CoV-2. These proteins include the viral receptor, angiotensin-converting enzyme 2 (ACE2), and the proteases, transmembrane serine protease 2 (TMPRSS2) and furin. A number of studies have reported cell-type-specific expression of the genes encoding these molecules. However, less is known about the protein expression of these molecules. We assessed the suitability of primary human bronchial epithelial (HBE) cells maintained in an air-liquid interface (ALI) as an experimental system for studying SARS-CoV-2 infection in vitro. During cellular differentiation, we measured the expression of ACE2, TMPRSS2, and furin over progressive ALI days by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining. We also explored the effect of the fibrotic cytokine TGF-ß on the expression of these proteins in well-differentiated HBE cells. Like ACE2, TMPRSS2 and furin proteins are localized in differentiated ciliated cells, as confirmed by immunofluorescence staining. These data suggest that well-differentiated HBE cells maintained in ALI are a reliable in vitro system for investigating cellular mechanisms of SARS-CoV-2 infection. We further identified that the profibrotic mediators, TGF-ß1 and TGF-ß2, increase the expression of furin, which is a protease required for the cellular entry of SARS-CoV-2.

Subtype-specific differences in Gag-protease replication capacity of HIV-1 isolates from East and West Africa.

BACKGROUND: The HIV-1 epidemic in sub-Saharan Africa is heterogeneous with diverse unevenly distributed subtypes and regional differences in prevalence. Subtype-specific differences in disease progression rate and transmission efficiency have been reported, but the underlying biological mechanisms have not been fully characterized. Here, we tested the hypothesis that the subtypes prevalent in the East Africa, where adult prevalence rate is higher, have lower viral replication capacity (VRC) than their West African counterparts where adult prevalence rates are lower. RESULTS: Gag-protease sequencing was performed on 213 and 160 antiretroviral-naïve chronically infected participants from West and East Africa respectively and bioinformatic tools were used to infer subtypes and recombination patterns. VRC of patient-derived gag-protease chimeric viruses from West (n = 178) and East (n = 114) Africa were determined using a green fluorescent protein reporter-based cell assay. Subtype and regional differences in VRC and amino acid variants impacting VRC were identified by statistical methods. CRF02_AG (65%, n = 139), other recombinants (14%, n = 30) and pure subtypes (21%, n = 44) were identified in West Africa. Subtypes A1 (64%, n = 103), D (22%, n = 35), or recombinants (14%, n = 22) were identified in East Africa. Viruses from West Africa had significantly higher VRC compared to those from East Africa (p < 0.0001), with subtype-specific differences found among strains within West and East Africa (p < 0.0001). Recombination patterns showed a preference for subtypes D, G or J rather than subtype A in the p6 region of gag, with evidence that subtype-specific differences in this region impact VRC. Furthermore, the Gag A83V polymorphism was associated with reduced VRC in CRF02_AG. HLA-A*23:01 (p = 0.0014) and HLA-C*07:01 (p = 0.002) were associated with lower VRC in subtype A infected individuals from East Africa. CONCLUSIONS: Although prevalent viruses from West Africa displayed higher VRC than those from East Africa consistent with the hypothesis that lower VRC is associated with higher population prevalence, the predominant CRF02_AG strain in West Africa displayed higher VRC than other prevalent strains suggesting that VRC alone does not explain population prevalence. The study identified viral and host genetic determinants of virus replication capacity for HIV-1 CRF02_AG and subtype A respectively, which may have relevance for vaccine strategies.

Rifabutin pharmacokinetics and safety among TB/HIV-coinfected children receiving lopinavir/ritonavir-containing second-line ART.

BACKGROUND: Treatment options are limited for TB/HIV-coinfected children who require PI-based ART. Rifabutin is the preferred rifamycin for adults on PIs, but the one study evaluating rifabutin with PIs among children was stopped early due to severe neutropenia. METHODS: We evaluated rifabutin safety and plasma pharmacokinetics among coinfected children 3-15 years of age receiving rifabutin 2.5 mg/kg daily with standard doses of lopinavir/ritonavir. The AUC0-24 at 2, 4 and 8 weeks after rifabutin initiation was described using intensive sampling and non-compartmental analysis. Clinical and laboratory toxicities were intensively monitored at 12 visits throughout the study. RESULTS: Among 15 children with median (IQR) age 13.1 (10.9-14.0) years and weight 25.5 (22.3-30.5) kg, the median (IQR) rifabutin AUC0-24 was 5.21 (4.38-6.60) µg·h/mL. Four participants had AUC0-24 below 3.8 µg·h/mL (a target for the population average exposure) at week 2 and all had AUC0-24 higher than 3.8 µg·h/mL at the 4 and 8 week visits. Of 506 laboratory evaluations during rifabutin, grade 3 and grade 4 abnormalities occurred in 16 (3%) and 2 (0.4%) instances, respectively, involving 9 (60%) children. Specifically, grade 3 (n = 4) and grade 4 (n = 1) neutropenia resolved without treatment interruption or clinical sequelae in all patients. One child died at week 4 of HIV-related complications. CONCLUSIONS: In children, rifabutin 2.5 mg/kg daily achieved AUC0-24 comparable to adults and favourable HIV and TB treatment outcomes were observed. Severe neutropenia was relatively uncommon and improved with ongoing rifabutin therapy. These data support the use of rifabutin for TB/HIV-coinfected children who require lopinavir/ritonavir.

Low levels of HIV-1 drug resistance mutations in patients who achieved viral re-suppression without regimen switch: a retrospective study.

BACKGROUND: We identified a HIV-positive cohort in virologic failure (VF) who re-suppressed without drug switch. We characterized their drug resistance mutations (DRM) and adherence profiles to learn how to better manage HIV drug resistance. A retrospective cohort study utilizing clinical data and stored samples. Patients received ART at three Nigerian treatment centres. Plasma samples stored when they were in VF were genotyped. RESULT: Of 126 patients with samples available, 57 were successfully genotyped. From ART initiation, the proportion of patients with adherence ≥90% increased steadily from 54% at first high viral load (VL) to 67% at confirmed VF, and 81% at time of re-suppressed VL. Sixteen (28%) patients had at least one DRM. Forty-six (81%) patients had full susceptibility to the three drugs in their first-line (1 L) regimen. Thirteen (23%) were resistant to at least one antiretroviral drug but three were resistant to drugs not used in Nigeria. Ten patients had resistance to their 1 L drug(s) and six were fully susceptible to the three drugs in the recommended second-line regimen. CONCLUSION: This cohort had little drug resistance mutations. We conclude that if adherence is not assured, patients could exhibit virologic failure without having developed mutations associated with drug resistance.

Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART.

BACKGROUND: TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. METHODS: Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. RESULTS: Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9-5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%-25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1-4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. CONCLUSIONS: With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

Association between HIV-1 subtype and drug resistance in Nigerian infants.

Background: Many lines of evidence point to HIV-1 subtype-specific differences in the development of drug resistance mutations. While variation between subtype C and others has been extensively explored, there has been less emphasis on subtypes common to West Africa. We examined a previously described national survey of pretreatment drug resistance in HIV-1-infected Nigerian children aged <18 months, to explore the association between subtypes and patterns of resistance. Methods: Five hundred and forty-nine dried blood spots, from 15 early infant diagnostic facilities in Nigeria, were amplified and HIV-1 polymerase was sequenced. Four hundred and twenty-four were analysed for surveillance drug resistance mutations (SDRMs). Associations between subtype and SDRMs were evaluated by Fisher's exact test and logistic regression analysis, controlling for geographical region and exposure. Results: Using the sub-subtypes of HIV-1 G defined by Delatorre et al. (PLoS One 2014. 9: e98908) the most common subtypes were CRF02_AG (174, 41.0%), GWA-I (128, 30.2%), GWA-II (24, 5.7%), GCA (11, 2.6%), A (21, 5.0%) and CRF06_cpx (18, 4.2%). One hundred and ninety infants (44.8%) had ≥1 NNRTI mutation, 92 infants (21.7%) had ≥1 NRTI mutation and 6 infants (1.4%) had ≥1 PI mutation. By logistic regression, 67N was more common in GWA-II/GCA than CRF02_AG (OR 12.0, P = 0.006), as was 70R (OR 23.1, P = 0.007), 184I/V (OR 2.92, P = 0.020), the presence of ≥1 thymidine analogue mutation (TAM) (OR 3.87, P = 0.014), ≥1 type 2 TAM (OR 7.61, P = 0.001) and ≥1 NRTI mutation (OR 3.26, P = 0.005). Conclusions: This dataset reveals differences among SDRMs by subtype; in particular, between the GWA-II and GCA subclades, compared with CRF02_AG and GWA-I.

Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa.

Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses.IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

The role of point-of-care viral load monitoring in achieving the target of 90% suppression in HIV-infected patients in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: The Joint United Nations Programme on HIV/AIDS 90-90-90 goal envisions 90% of all people receiving antiretroviral therapy to be virally suppressed by 2020. Implied in that goal is that viral load be quantified for all patients receiving treatment, which is a challenging undertaking given the complexity and high cost of standard-of-care viral load testing methods. Recently developed point-of-care viral load testing devices offer new promise to improve access to viral load testing by bringing the test closer to the patient and also returning results faster, often same-day. While manufactures have evaluated point-of-care assays using reference panels, empiric data examining the impact of the new technology against standard-of-care monitoring in low- and middle-income settings are lacking. Our goal in this trial is to compare a point-of-care to standard-of-care viral load test on impact on various clinical outcomes as well to assess the acceptability and feasibility of using the assay in a resource-limited setting. METHODS: Using a two-arm randomized control trial design, we will enroll 794 patients from two different HIV treatment sites in Nigeria. Patients will be randomized 1:1 for point-of-care or standard-of-care viral load monitoring (397 patients per arm). Following initiation of treatment, viral load will be monitored at patients' 6- and 12-month follow-up visits using either point-of-care or standard-of-care testing methods, based on trial assignment. The monitoring schedule will follow national treatment guidelines. The primary outcome measure in this trial is proportion of patients with viral suppression at month 12 post-initiation of treatment. The secondary outcome measures encompass acceptability, feasibility, and virologic impact variables. DISCUSSION: This clinical trial will provide information on the impact of using point-of-care versus standard-of-care viral load testing on patient clinical outcomes; the study will also supply data on the acceptability and feasibility of point-of-care viral load monitoring in a resource-limited setting. If this method of testing is acceptable and feasible, and also superior to standard of care, the results of the trial and the information gathered will inform future scaled implementation and further optimization of the clinic-laboratory network that is critical for monitoring achievement of the 90-90-90 goals. TRIAL REGISTRATION: US National Institutes of Health Clinical Trials.gov: NCT03533868 . Date of Registration: 23 May 2018. Protocol Version: 10. Protocol Date: 30 March 2018.

Continued Transmission of Zika Virus in Humans in West Africa, 1992-2016.

First identified in 1947 in Uganda, Zika virus (ZIKV) has remained largely unstudied until the recent outbreak in Latin America. This study aimed to measure the prevalence of ZIKV in febrile patients in Senegal and Nigeria in samples collected from 1992 to 2016. The seroprevalence of ZIKV was 6.2% based on ZIKV immunoglobulin M and negative for dengue reactivity. ZIKV envelope was amplified from 4 samples. Phylogenetic analysis showed that the ZIKVs belonged to the African lineage, grouping with either the Nigerian or MR766 sublineages. This study provides evidence that ZIKV has been silently circulating in West Africa for 2 decades.

Drug resistance patterns following pharmacy stock shortage in Nigerian Antiretroviral Treatment Program.

BACKGROUND: For patients on antiretroviral therapy (ART), treatment interruptions can impact patient outcomes and result in the accumulation of drug resistance mutations leading to virologic failure. There are minimal published data on the impact of an ART stock shortage on development of drug resistance mutations (DRMs). In this report, we evaluate data from patients enrolled in the Government of Nigeria National ART Program that were receiving treatment at the time of a national drug shortage in late 2003. METHODS: We conducted a cross-sectional evaluation of samples collected between December 2004 and August 2005 from ART patients in virologic failure that either had a treatment interruption or did not during the late 2003 drug shortage period at the Jos University Teaching Hospital (JUTH). Plasma virus was genotyped, sequence data were edited and analyzed, and mutation profiles were categorized to evaluate predicted drug susceptibility. Data were analyzed to examine factors associated with development of resistance mutations. A genotypic sensitivity score to the alternate recommended regimen was computed to assess drug susceptibility if regimens were changed. RESULTS: A total of 56 patients were included in this evaluation (28 interrupted, 28 uninterrupted). Patients in the interrupted group had more DRMs than those in the uninterrupted group (p < 0.001); interrupted patients were more likely than uninterrupted patients to have one or more TAM-2 mutations (57.1% interrupted vs. 21.3% uninterrupted; p = 0.04). There was a statistically significant difference in resistance to both d4T (53.7% interrupted vs. 17.9 uninterrupted; p = 0.011) and AZT (64.3% interrupted vs. 25.0% uninterrupted; p = 0.003) by drug interruption status. Examining genotypic sensitivity scores, we found that 67.9% of the interrupted patients, as compared to 25.0% of the uninterrupted patients, did not have full susceptibility to one drug in the regimen to which guidelines recommended they be switched (p = 0.001). DISCUSSION: In this small observational study, we found evidence of a difference in resistance profiles and ART susceptibility between those that were stocked-out of drug versus those that were not. We believe that these data are relevant for many other low- and middle-income countries (LMIC) that also experienced similar ART shortages as they rapidly scaled up their national programs.

Superior Effectiveness of Zidovudine Compared With Tenofovir When Combined With Nevirapine-based Antiretroviral Therapy in a Large Nigerian Cohort.

BACKGROUND: Despite sparse efficacy data, tenofovir-emtricitabine or tenofovir-lamivudine plus nevirapine is used in many resource-constrained settings. METHODS: This retrospective cohort study included patients initiating nevirapine-based antiretroviral therapy (ART) with either tenofovir-emtricitabine or lamivudine (tenofovir group) or zidovudine-lamivudine (zidovudine group). Clinical, virologic, and immunologic evaluations were performed at baseline and every 6 months. Virologic failure was defined as 2 consecutive human immunodeficiency virus (HIV)-RNA values >1000 copies/mL. Patients were included from ART initiation until time of failure, regimen switch, discontinuation, or last HIV-RNA measurement. Cox proportional hazards regression was used to model factors influencing time to failure. Bias due to dependent censoring was investigated via inverse probability weighted pooled logistic regression. RESULTS: A total of 5547 patients were evaluated; 1484 (26.8%) were in the tenofovir group and 4063 (73.2%) were in the zidovudine group. In the adjusted model, tenofovir regimen (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.21-1.79) and higher baseline log10 HIV-RNA (HR, 1.15; 95% CI, 1.03-1.28) were associated with virologic failure. Higher baseline log10 CD4+ cell count (HR, 0.50; 95% CI, .40-.63) and increasing age (HR, 0.98; 95% CI, .97-.99) decreased the risk of virologic failure. Inverse probability weighting results were consistent with the primary analysis. CONCLUSIONS: Compared with zidovudine-lamivudine, the use of tenofovir-lamivudine or emtricitabine in combination with nevirapine was a strong predictor of virologic failure in our cohort, which was not explained by other risk factors or criteria for regimen selection.

Association of Bacterial vaginosis and other Sexually Transmitted Infections with HIV among pregnant women in Nigeria.

OBJECTIVES: To determine the association of Bacterial vaginosis (BV) and other sexually transmissible infections (STIs) with HIV prevalence among pregnant women in Jos, Nigeria. METHODS: This was a cross- sectional study of pregnant women who participated in the Prevention of Mother-to-Child Transmission of HIV program of the AIDS Prevention Initiative in Nigeria, between April 2002 and July 2004, at the Jos University Teaching Hospital in Jos, Nigeria. Blood, high vaginal and endocervical samples were obtained for diagnosis of HIV, BV and other STIs. Data were analyzed for prevalence of HIV, BV and other STIs. Univariate and multivariate logistic regression models generated unadjusted and adjusted odds ratios (OR) as well as 95% confidence intervals (CI) of the association of BV and other STIs with HIV prevalence. P value <0.05 was considered statistically significant. RESULTS: A total of 4,046 pregnant women were studied and 97.6% (3,950/4,046) had complete laboratory records for analysis. The prevalence of HIV was 8.2% (CI: 7.4-9.1); BV 11.9% (CI: 10.9-12.9); Candida 10.7% (CI: 9.7-11.7); mixed infection of BV and Candida 2.8% (CI: 2.3-3.4); Trichomonads 0.6% (CI: 0.3-0.8) and syphilis 0.35% (0.16-0.54). BV, Candida, mixed BV and Candida; and Trichomonads were independently associated with HIV infection [adjusted OR (95% CI), 2.9 (CI: 2.2-3.9); 2.0 (CI: 1.5-2.9); 3.4 (CI: 2.0-5.6), and 3.3 (CI: 1.1-9.7) respectively]. CONCLUSION: HIV prevalence is higher among pregnant women who have BV, Candida and Trichomonads vaginal infections compared with women who have no evidence of infection. The practice of routine screening for BV and other STIs among pregnant women as a strategy for identifying women at risk for prevalent HIV infection should be sustained/ encouraged and the syndromic management of STIs should be integrated into all antenatal care management protocols in antenatal clinics in order to curb the epidemic of heterosexual HIV transmission.

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

The HIV-2 proviral landscape is dominated by defective proviruses.

BACKGROUND: Compared with HIV-1 infection, HIV-2 infection is associated with a slower progression to AIDS. Understanding the persistence of HIV-2 infection might inform the mechanisms responsible for differences in the pathogenicity of HIV-2 versus HIV-1. METHODS: In this study, we analyzed the genetic composition of the proviral reservoir in archived blood samples collected from 13 untreated HIV-2-infected adults from Senegal. We used single-genome, near-full-length individual proviral sequencing (FLIP-Seq) to assess the relative frequency of intact and defective proviruses. RESULTS: Ten out of 13 (77%) study participants demonstrated virologic suppression (<90 HIV RNA copies/ml) while the remaining 3 (23%) had detectable HIV RNA. We obtained 363 proviral sequences from peripheral blood mononuclear cells (PBMCs) from the 13 study participants. Within these sequences, 342 (94%) defective proviruses were detected. Twenty-one (6%) intact proviruses were detected from three study participants, with one study participant displaying a large clone consisting of 16 genome-intact sequences. CONCLUSION: This data suggests that similar to HIV-1 infection, the proviral landscape of HIV-2 is dominated by defective proviruses.