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Objective:In a multicountry prospective cohort of persons with HIV from six countries between 2007 and 2015, we evaluated long-term outcomes of first-line non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART), and risk factors for loss-to-follow-up, mortality, virological failure, and incomplete CD4 +T-cell recovery.Methods:We calculated cumulative incidence of lost-to-follow-up, death, virological failure (VL ≥ 1000 cps/ml) and incomplete CD4 +T-cell recovery (+T-cell count was 135 (IQR 63-205)/μl. Total follow-up time was 7208 person-years (median 24.3 months, IQR 18.7-58.3). Deaths by any cause and loss to follow-up occurred mostly during the first year of ART (84%, 201/240 and 56%, 199/353, respectively). During their first 6 years of ART, 71% (95% confidence interval [CI] 69.0-73.7) were retained on first-line, and among those 90-93% sustained viral suppression (+T-cell recovery was incomplete in 60% (220/363) of participants. The risk factors associated with poor outcomes during long-term ART were: for loss-to-follow-up, recent VL ≥1000 cps/ml, recent CD4 +T-cell count ≤50 cells/μl, age +T-cell count ≤50 cells/μl; and, for virological failure, age +T-cell count ≤200 cells/μl, poor adherence, male sex, and low-level viremia.Conclusion:To achieve long-term ART success towards the UNAIDS targets, early ART initiation is crucial, coupled with careful monitoring and retention support, particularly in the first year of ART. Male and youth-centred care delivery models are needed to improve outcomes for those vulnerable groups.

Introduction: To achieve viral suppression among more than 90% of people on antiretroviral therapy (ART), improved understanding is warranted of the modifiable causes of HIV viremic episodes. We assessed the relative contributions of drug-resistance, nonadherence and low-level viremia (LLV) (viral load 50–999 cps/ml) on viremic episodes in sub-Saharan Africa. Methods: In a multicountry adult cohort initiating nonnucleoside reverse transcriptase inhibitor-based first-line ART, viremic episodes (viral load ≥1000 cps/ml) were classified as first, viral nonsuppression at 12 months; second, virological rebound at 24 months (after initial viral suppression at 12 months); third, failure to achieve viral resuppression at 24 months (after viremic episode at 12 months). We used adjusted odds ratios from multivariable logistic regression to estimate attributable fractions for each risk factor. Results: Of 2737 cohort participants, 1935 had data on pretreatment drug resistance (PDR) and at least 1 viral load outcome. Viral nonsuppression episodes [173/1935 (8.9%)] were attributable to nonadherence in 30% (35% in men vs. 24% in women) and to PDR to nonnucleoside reverse transcriptase inhibitors in 10% (15% in women vs. 6% in men). Notably, at contemporary PDR prevalences of 10–25%, PDR would explain 13–30% of viral nonsuppression. Virological rebound episodes [96/1515 (6.3%)] were mostly attributable to LLV (29%) and nonadherence (14%), and only rarely to PDR (1.1%). Failures to achieve viral resuppression [66/81 (81.5%)] were mostly attributable to the presence of acquired drug resistance (34%) and only rarely to nonadherence (2.4%). Conclusion: Effective adherence interventions could substantially reduce viral nonsuppression (especially in men) and virological rebound (especially during LLV), but would have limited effect on improving viral resuppression. Alternative ART regimens could circumvent PDR and acquired resistance.

In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess the associations between PAU, PDR and VF (defined as viral load ≥400 cps/mL). Causal mediation analysis was used to assess the proportion of the effect of PAU on VF that could be eliminated by intervening on PDR. Of 2737 participants, 122 (4.5%) had a history of PAU. Participants with PAU had a 7.2-fold (95% CI 4.4–11.7) risk of carrying PDR and a 3.1-fold (95% CI 1.6–6.1) increased risk of VF, compared to antiretroviral-naïve participants. Controlling for PDR would eliminate nearly half the effect of PAU on the risk of VF. Patients with a history of PAU are at increased risk of ART failure, which is to a large extent attributable to PDR. These findings support the recent WHO recommendations for use of differentiated, non-NNRTI-based empiric first-line therapy in patients with PAU.

OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).DESIGN: Multicountry prospective cohort.METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4 cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4 strata.RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4 cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4 cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4 cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4 cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4 cell count less than 200 cells/μl, and comparable across the higher CD4 strata. Older age, male sex, and lower pre-ART CD4 cell count were strongly associated with suboptimal immune recovery.CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4 cell count.

BACKGROUND: Implementation of ultrasensitive HIV drug resistance tests for routine clinical use is hampered by uncertainty about the clinical relevance of drug-resistant minority variants. We assessed different detection thresholds for pretreatment drug resistance to predict an increased risk of virological failure.METHODS: We did a case-control study nested within a prospective multicountry cohort. Our study included patients from 12 clinical sites in Kenya, Nigeria, South Africa, Uganda, and Zambia. We defined cases as patients with virological failure (ie, those who had either viral load ≥400 copies per mL at 12 months or had switched to second-line antiretroviral therapy [ART] as a result of virological failure before 12 months) and controls as those with viral suppression (viral load FINDINGS: Paired viral load results before ART and at month 12 of follow-up were available from 1896 participants. We identified 178 patients with virological failure and selected 338 matched controls. We excluded 117 patients from pretreatment drug resistance analysis; therefore, 152 cases of virological failure and 247 controls were included in the final analysis. With the IAS-USA mutation list, at a detection threshold of 20% or more in patients with pretreatment drug resistance, the adjusted odds ratio (OR) for virological failure was 9·2 (95% CI 4·2-20·1) compared with those without pretreatment drug resistance. Lowering the threshold resulted in adjusted ORs of virological failure of 6·8 (95% CI 3·3-13·9) at the 10% threshold, 7·6 (3·4-17·1) at the 5% threshold, and 4·5 (2·0-10·2) at the 1% threshold. Lowering the detection threshold from 20% improved the sensitivity (ie, ability to identify cases) from 12% (n=18) to 13% (n=19) at detection threshold 10%, to 15% (n=23) at detection threshold 5%, and to 17% (n=26) at detection threshold 1%, but caused a slight reduction in specificity (ie, ability to identify controls) from 98% (n=241) to 96% (n=238) at the 10% threshold, 96% (n=236) at the 5% threshold, and a larger reduction to 92% (n=227) at the 1% threshold. Diagnostic ORs were 5·4 (95% CI 2·1-13·9) at the 20% threshold, 3·8 (1·7-8·6) at the 10% threshold, 3·8 (1·8-8·1) at the 5% threshold, and 2·3 (1·2-4·2) at the 1% threshold. Use of the Stanford HIVDB genotypic sensitivity scores yielded similar ORs for virological failure, sensitivities, specificities, and diagnostic ORs.INTERPRETATION: Ultrasensitive resistance testing for pretreatment drug resistance improved identification of people at risk of virological failure; however, this came with a reduction in our ability to identify people with viral suppression, especially at very low thresholds. Further modelling is needed to estimate the optimal trade-off for the 5% and 20% thresholds, balancing improved case finding against unnecessary regimen switching.FUNDING: The Netherlands Ministry of Foreign Affairs, IrsiCaixa, and European Union.

Introduction: HIV infected patients on antiretroviral therapy (ART) are at risk of developing nephropathy and therefore require monitoring of renal function. Some medications used in the management of HIV, opportunistic infections (OIs) and other comorbidities are nephrotoxic and may further compromise renal function, underlining the importance of regular monitoring of renal function. This study was designed to determine the incidence of nephropathy in HIV infected patients on antiretroviral therapy (ART) at Newlands Clinic and to determine the associated risk factors. Methodology: A retrospective cohort study was conducted involving 1986 HIV-1 infected participants who were commenced on ART between January 2007 and December 2013 at Newlands Clinic. The majority of participants were female (1340 (67.5%)). All participants were aged 18 or older at ART commencement. Participants with pre-existing nephropathy at baseline were excluded. Nephropathy was defined as two consecutive calculated creatinine clearances (CrCl) less than 60 ml/min by the Cockcroft-Gault equation, or two consecutive urine dipsticks positive for protein (≥30 g/L albumin). Data collected during routine patient visits were exported from the clinic’s database and analysed for incidence of nephropathy and risk factors. Results: During the follow-up period, 93 of the 1986 participants (4.7%) developed nephropathy. The estimated incidence rate (IR) of nephropathy was 1.45/100 person years (CI: 1.17 - 1.78). In the multivariate analysis, statistically significant risk factors were baseline age > 45 (HR 2.30, CI: 1.50 - 3.55), diabetes mellitus (HR 4.12, CI: 1.75 - 9.69), pulmonary tuberculosis (HR 2.00, CI: 1.28 - 3.12), and HIV wasting syndrome (HR 2.72, CI: 1.30 - 5.68). Conclusion: The incidence of nephropathy was low in this cohort. The traditional risk factors for renal disease; older age and diabetes mellitus were significant, as well as HIV wasting syndrome and pulmonary tuberculosis. HIV care should be complimented with proper diabetic care and patients that develop pulmonary tuberculosis, HIV wasting syndrome or are initiated on ART above 45 years require regular monitoring for early detection of nephropathy.

Objectives Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. Methods HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. Results At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P Conclusions Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Background Zimbabwe set up 12 sentinel sites to monitor HIV drug resistance (HIVDR) following the international standards for prevention of HIVDR from 2008 to 2010. Methods Participants were consecutively enrolled. Blood was collected and used for CD4 count, viral load (VL) and pre-treatment DR (PDR) tests besides routine baseline tests. We analyzed the characteristics of participants enrolled into the survey and estimated the point prevalence of PDR and its associated factors among ART initiators in a cross-sectional analysis using the baseline data collected from a prospective cohort in 12 purposefully selected sentinel sites. Results A total of 1728 participants (96 % response rate) were enrolled and 1610 had complete data. Of the 1610 there were more females (68.7 %) than males (31.3 %). The median CD4 count was 168 cells/mm3 with males having lower values (P = 0.003). Ninety-six percent of participants had a VL ≥ 1000 copies/ml and the median VL was 128,000. Previous exposure to antiretroviral drugs (ARVs) was mainly through PMTCT (5 % of the participants). Overall, PDR mutations were detected in 6.3 % (95 % CI 5.2–7.7) of the 1480 successfully genotyped participants. However, the prevalence of PDR mutations was double for those with previous exposure (12.1 %) to ARVs compared with those without previous exposure (5.7 %, P = 0.002). Conclusions The results show a moderate level of PDR prevalence among ART initiators. To maintain the efficacy of the current first-line regimens, there is need to strengthen all HIVDR prevention efforts and to conduct further studies to investigate optimal strategies that can prolong the efficacy of first-line ARV regimens in the country.

Little is known about the effect of human immunodeficiency virus type 1 (HIV-1) resistance mutations present at time of regimen switch on the response to second-line antiretroviral therapy in Africa. In adults who switched to boosted protease inhibitor-based regimens after first-line failure, HIV-RNA and genotypic resistance testing was performed at switch and after 12 months. Factors associated with treatment failure were assessed using logistic regression. Of 243 participants, 53 were predicted to receive partially active second-line regimens due to drug resistance. The risk of treatment failure was, however, not increased in these participants. In this African cohort, boosted protease inhibitors successfully resuppressed drug-resistant HIV after first-line failure.

The PharmAccess African Studies to Evaluate Resistance (PASER) network was established as a collaborative partnership of clinical sites, laboratories, and research groups in 6 African countries; its purpose is to build research and laboratory capacity in support of a coordinated effort to assess population-level acquired and transmitted human immunodeficiency virus type-1 drug resistance (HIVDR), thus contributing to the goals of the World Health Organization Global HIV Drug Resistance Network. PASER disseminates information to medical professionals and policy makers and conducts observational research related to HIVDR. The sustainability of the network is challenged by funding limitations, constraints in human resources, a vulnerable general health infrastructure, and high cost and complexity of molecular diagnostic testing. This report highlights experiences and challenges in the PASER network from 2006 to 2010.

Background. As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. Methods. HIV-1–infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. Results. Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based (hazard ratio, 7.10; 95% confidence interval, 3.40–14.83; P < .001) or PI-based (7.59; 3.02–19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49–17.98; P < .001), and suboptimal adherence (3.05; 1.71–5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. Conclusions. Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Background. After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. Methods. In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) >1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to >1 prescribed drug. We assessed the effect of pretreatment drug resistance on all-cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. Results. Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49-9.68; P =. 005) but was not associated with mortality (aHR 0.75, 95% CI,. 24-2.35; P =. 617) or new AIDS events (aHR 1.06, 95% CI,. 68-1.64; P =. 807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL > 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL > 1000 cps/mL and >1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. Conclusions. Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices.

BACKGROUND There are limited published data on the outcomes of infants starting antiretroviral therapy (ART) in routine care in Southern Africa. This study aimed to examine the baseline characteristics and outcomes of infants initiating ART. METHODS We analyzed prospectively collected cohort data from routine ART initiation in infants from 11 cohorts contributing to the International Epidemiologic Database to Evaluate AIDS in Southern Africa. We included ART-naive HIV-infected infants aged

Introduction:voluntary Medical Male Circumcision (VMMC) is the surgical removal of the foreskin by a trained health worker. VMMC was introduced in Zimbabwe in 2009. It is of concern that the programme performance has been below expectations nationally and in Mazowe district. Zimbabwe is unlikely to meet its 2015 target of circumcising 1 200 000 men aged between 15 and 29 years and unlikely to enjoy maximum benefits of VMMC which include prevention of HIV, sexually transmitted infections and cervical cancer. We therefore broadly aimed at identifying factors influencing the level of VMMC uptake in Mazowe district. Methods:an analytic cross-sectional study was carried out in Mazowe district. A multi-stage probability sampling strategy was used to select 300 men aged between 18 and 49 years. Pretested interviewer administered questionnaires, key informant interviews and focus group discussions were used to collect data. Quantitative data was analysed using Epi info where odds ratios and p-values were calculated. Qualitative data was analysed thematically. Results:being of Shona origin (AOR= 7.69 (95%CI 1.78-33.20)), fear of pain (AOR= 7.09 (95%CI 2.58-19.47)) and fear of poor wound healing (AOR= 2.68 (95%CI 1.01-7.08)) were independently associated with being uncircumcised while having a circumcised friend and encouragement by a friend or relative were independently associated with being circumcised. Conclusion:fear of pain, fear of poor wound healing and encouragement by a friend or relative were associated with circumcision status. Widening use of surgical devices and third part referrals may assist in scaling up the programme.

Background More than half of hypertensive patients reviewed at Lupane District Hospital during the first half of 2011 had uncontrolled hypertension. This prompted an investigation on the prevalence of uncontrolled hypertension and associated factors among hypertensives on treatment. Methods Analytical cross-sectional study was conducted. Three hundred fifty-four consenting participants were consecutively selected from eligible hypertensive patients on treatment attending the outpatients department at Lupane District Hospital for their reviews. An interviewer administered questionnaire adapted from the World Health Organization was used to collect data on risk factors. Blood pressure and anthropometric measurements were taken as per World Health Organization guidelines. Uncontrolled hypertension was defined as systolic blood pressure of ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg in a patient taking anti-hypertensive medication. Results Mean systolic BP was 151.0 mmHg and mean diastolic BP was 92.6 mmHg. Prevalence of uncontrolled hypertension was (238) 67.2%. Independent risk factors for uncontrolled hypertension were obesity (AOR 3.28, 95% CI 1.39-7.75) and adding salt to food at the table (AOR 2.77, 95% CI 1.41-5.43) whilst being compliant with the drug treatment regimen (AOR 0.34, 95% CI 0.16-0.72) and having received health education on hypertension (AOR 0.49, 95% CI 0.25- 0.97) were protective against uncontrolled hypertension. Conclusion There prevalence of uncontrolled hypertension is high despite all the participants being on treatment. The findings suggest that interventions at the patient, the provider and the health delivery system are needed to improve hypertension control in Lupane, Zimbabwe.

We evaluated a low-cost virological failure assay (VFA) on plasma and dried blood spot (DBS) specimens from HIV-1 infected patients attending an HIV clinic in Harare. The results were compared to the performance of the ultrasensitive heat-denatured p24 assay (p24). The COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0, served as the gold standard. Using a cutoff of 5,000 copies/mL, the plasma VFA had a sensitivity of 94.5% and specificity of 92.7% and was largely superior to the VFA on DBS (sensitivity = 61.9%; specificity = 99.0%) or to the p24 (sensitivity = 54.3%; specificity = 82.3%) when tested on 302 HIV treated and untreated patients. However, among the 202 long-term ART-exposed patients, the sensitivity of the VFA decreased to 72.7% and to 35.7% using a threshold of 5,000 and 1,000 RNA copies/mL, respectively. We show that the VFA (either on plasma or on DBS) and the p24 are not reliable to monitor long-term treated, HIV-1 infected patients. Moreover, achieving acceptable assay sensitivity using DBS proved technically difficult in a less-experienced laboratory. Importantly, the high level of virological suppression (93%) indicated that quality care focused on treatment adherence limits virological failure even when PCR-based viral load monitoring is not available.

The aim of this unmatched case-control study was to obtain information on risk factors and health-seeking behavior of men with sexually transmitted diseases (STDs) attending primary care clinics. Cases consisted of 256 consecutive men with genital ulcer disease (GUD) and 256 with other STDs. Control subjects (N = 256) were recruited from every third man with non-STD-related complaints. All subjects were at least 15 years of age. A structured questionnaire was administered. GUD cases reported more frequent sexual intercourse with a commercial sex worker (odds ratio [OR] = 17.4; 95% confidence interval [CI] = 7.8-40.0) and a recent new sexual contact (OR = 6.7; CI = 3.3-14.1). Similarly STD cases reported more frequent sexual contact with a commercial sex worker (OR = 3.4; CI = 2.0-5.6) and a recent new sexual contact (OR = 7.9; CI = 3.9-16.3). Reported condom use was

To investigate the incidence of selected opportunistic infections (OIs) and cancers and the role of a history of tuberculosis (TB) as a risk factor for developing these conditions in HIV-infected patients starting antiretroviral treatment (ART) in Southern Africa.Five ART programmes from Zimbabwe, Zambia and South Africa participated. Outcomes were extrapulmonary cryptococcal disease (CM), pneumonia due to Pneumocystis jirovecii (PCP), Kaposi's sarcoma and Non-Hodgkin lymphoma. A history of TB was defined as a TB diagnosis before or at the start of ART. We used Cox models adjusted for age, sex, CD4 cell count at ART start and treatment site, presenting results as adjusted hazard ratios (aHR) with 95% confidence intervals (CI).We analysed data from 175,212 patients enrolled between 2000 and 2010 and identified 702 patients with incident CM (including 205 with a TB history) and 487 with incident PCP (including 179 with a TB history). The incidence per 100 person-years over the first year of ART was 0.48 (95% CI 0.44-0.52) for CM, 0.35 (95% CI 0.32-0.38) for PCP, 0.31 (95% CI 0.29-0.35) for Kaposi's sarcoma and 0.02 (95% CI 0.01-0.03) for Non-Hodgkin lymphoma. A history of TB was associated with cryptococcal disease (aHR 1.28, 95% CI 1.05-1.55) and Pneumocystis jirovecii pneumonia (aHR 1.61, 95% CI 1.27-2.04), but not with Non-Hodgkin lymphoma (aHR 1.09, 95% CI 0.45-2.65) or Kaposi's sarcoma (aHR 1.02, 95% CI 0.81-1.27).Our study suggests that there may be interactions between different OIs in HIV-infected patients.

Background. Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. Methods. A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was > 1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. Results. HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried >= 1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with >= 1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. Conclusions. Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority

Background: The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. Methods: HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. Findings: Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p

Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART site factors known to favor the emergence of HIVDR. HIV drug resistance EWI monitoring was performed within the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) study, comprising 13 ART sites in 6 African countries. Early warning indicator assessment in the PASER network identified vulnerable aspects of ART programs and triggered interventions aimed at minimizing HIVDR emergence. Additionally, data suggest an advantage of medication possession ratio over on-time antiretroviral drug pickup in identifying patients at risk for HIVDR development.

BACKGROUND: Poor growth is an indication for antiretroviral therapy (ART) and a criterion for treatment failure. We examined variability in growth response to ART in 12 programs in Malawi, Zambia, Zimbabwe, Mozambique, and South Africa. METHODS: Treatment naïve children aged RESULTS: A total of 17 990 children (range, 238–8975) were followed for 36 181 person-years. At ART initiation, most children were underweight (50%) and stunted (66%). Lower baseline WAZ, HAZ, and WHZ were the most important determinants of faster catch-up growth on ART. WAZ and WHZ increased rapidly in the first year and stagnated or reversed thereafter, whereas HAZ increased continuously over time. Three years after starting ART, WAZ ranged from −2.80 (95% confidence interval [CI]: −3.66 to −2.02) to −1.98 (95% CI: −2.41 to −1.48) in children with a baseline z score < −3 and from −0.79 (95% CI: −1.62 to 0.02) to 0.05 (95% CI: −0.42 to 0.51) in children with a baseline WAZ ≥ −1. For HAZ, the corresponding range was −2.33 (95% CI: −2.62 to −2.02) to −1.27 (95% CI: −1.58 to −1.00) for baseline HAZ < −3 and −0.24 (95% CI: −0.56 to 0.15) to 0.84 (95% CI: 0.53 to 1.16) for HAZ ≥ −1. CONCLUSIONS: Despite a sustained growth response and catch-up growth in children with advanced HIV disease treated with ART, normal weights and heights are not achieved over 3 years of ART.

Summary Background There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance. Methods We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients. Findings 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62–204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6–6.7), ranging from 1.1% (two of 176; 0.0–2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5–17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9–14.2), compared with 3.5% (73 of 1866; 2.5–4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8–3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5–4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8–1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7–1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13–1.68; p=0.001). Interpretation The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up. Funding Ministry of Foreign Affairs of the Netherlands.

Objectives: This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. Methods: Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI crossresistance (≥2 TAMs or Q151M or K65R/K70E). Results: Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA