Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala

Objective: To assess the emergence of transmitted HIV-1 drug resistance (TDR) in Kampala, Uganda, 10 years after the scale-up of antiretroviral treatment (ART) and to compare with a previous survey among antenatal clinic attendees in 2007 (reporting 0% TDR). Design: A cross-sectional survey was conducted among newly HIV-1 diagnosed, antiretroviral-naive young adults attending two large voluntary counseling and testing centers within the geographic area of Kampala. Methods: Proxy criteria for recent HIV-1 infection were used as defined by the WHO. Population sequencing of the pol gene was performed on plasma samples with HIV-1 RNA at least 1000 copies/ml. Surveillance drug resistance mutations (SDRMs) were identified according to the 2009 WHO list for surveillance of TDR. HIV-1 subtypes were designated using maximum likelihood phylogenetic reconstruction. Results: Genotypic test results were obtained for 70 of 77 (90.9%) participants. SDRMs were identified in six samples yielding a prevalence of TDR of 8.6% (95% confidence interval 3.2-17.7%). Two had SDRMs to nucleoside reverse-transcriptase inhibitors (D67G and L210W), three had SDRMs to nonnucleoside reverse transcriptase inhibitors (G190A, G190S, and K101E), and one had SDRMs to protease inhibitors (N88D). Frequencies of HIV-1 subtypes were A (36/70, 51.4%), C (two of 70; 2.9%), D (23/70, 32.9%), and unique recombinant forms (nine of 70, 12.9%). Conclusion: This repeated survey suggests an increase in TDR in Kampala, compared with a previous survey. This finding justifies increased vigilance with respect to surveillance of TDR in areas in Africa where ART programs are rolled-out

Long-term virological outcomes of first-line antiretroviral therapy for HIV-1 in low- and middle-income countries: A systematic review and meta-analysis

Background.More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. Methods.We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. Results.Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. Conclusions.Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years

High Prevalence of HIV Drug Resistance Among Newly Diagnosed Infants Aged <18 Months: Results From a Nationwide Surveillance in Nigeria

BACKGROUND: WHO recommends protease-inhibitor-based first-line regimen in infants because of risk of drug resistance from failed prophylaxis used in prevention of mother-to-child transmission (PMTCT). However, cost and logistics impede implementation in sub-Saharan Africa, and >75% of children still receive nonnucleoside reverse transcriptase inhibitor-based regimen (NNRTI) used in PMTCT. METHODS: We assessed the national pretreatment drug resistance prevalence of HIV-infected children aged <18 months in Nigeria, using WHO-recommended HIV drug resistance surveillance protocol. We used remnant dried blood spots collected between June 2014 and July 2015 from 15 early infant diagnosis facilities spread across all the 6 geopolitical regions of Nigeria. Sampling was through a probability proportional-to-size approach. HIV drug resistance was determined by population-based sequencing. RESULTS: Overall, in 48% of infants (205 of 430) drug resistance mutations (DRM) were detected, conferring resistance to predominantly NNRTIs (45%). NRTI and multiclass NRTI/NNRTI resistance were present at 22% and 20%, respectively, while resistance to protease inhibitors was at 2%. Among 204 infants with exposure to drugs for PMTCT, 57% had DRMs, conferring NNRTI resistance in 54% and multiclass NRTI/NNRTI resistance in 29%. DRMs were also detected in 34% of 132 PMTCT unexposed infants. CONCLUSION: A high frequency of PDR, mainly NNRTI-associated, was observed in a nationwide surveillance among newly diagnosed HIV-infected children in Nigeria. PDR prevalence was equally high in PMTCT-unexposed infants. Our results support the use of protease inhibitor-based first-line regimens in HIV-infected young children regardless of PMTCT history and underscore the need to accelerate implementation of the newly disseminated guideline in Nigeria

HIV-HBV coinfection in Southern Africa and the effect of Lamivudine- Versus tenofovir-containing cART on HBV outcomes

BACKGROUND:: This study assessed HIV-hepatitis B virus (HBV) coinfection in southern Africa in terms of prevalence, viral characteristics, occult HBV, and the effect of lamivudine- versus tenofovir-containing first-line combination antiretroviral treatment (cART) on HBV-related outcomes. METHODS:: A multicenter prospective cohort of HIV-infected adults in Zambia and South Africa who initiated cART. Outcomes by month 12 on cART were immunological recovery, hepatitis B surface antigen (HBsAg) loss, viral suppression, and drug resistance. We used descriptive statistics, logistic regression, and linear mixed models. RESULTS:: Of the 1087 participants, 92 were HBsAg seropositive, yielding a sample-weighted prevalence of 7.4% (95% confidence interval: 5.6 to 9.2), with 76% genotype HBV-A1. The estimated CD4 recovery on cART was similar between HIV monoinfection and HIV-HBV coinfection groups and between lamivudine- and tenofovir-treated participants. HBsAg loss was documented in 20% (4/20) of lamivudine-treated and 18% (3/17) of tenofovir-treated participants (P = 0.305). Viral suppression (HBV-DNA < 20 IU/mL) was achieved in 61.5% (16/26) of lamivudine-treated and 71.4% (15/21) of tenofovir-treated participants (P = 0.477). HBV pol sequencing demonstrated M204I (n = 3) and N236T (n = 1) resistance-associated mutations in 4 of 8 (50%) lamivudine-treated participants and none in tenofovir-treated participants. Occult HBV infection was present in 13.3% before cART, but by month 12, HBV-DNA was below the limit of detection (<15 IU/mL) in 90.5% (19/21) of lamivudine-treated and 100% (18/18) of tenofovir-treated participants (P = 0.179). CONCLUSIONS:: Tenofovir-containing first-line cART is preferred for HIV-HBV coinfection in Africa because of a superior resistance profile relative to lamivudine monotherapy. Extended follow-up will be needed to determine long-term complications of occult HBV coinfection. Improved access to HBsAg screening and tenofovir is needed

Barriers to initiation of pediatric HIV treatment in Uganda: A mixed-method study

Although the advantages of early infant HIV diagnosis and treatment initiation are well established, children often present late to HIV programs in resource-limited settings. We aimed to assess factors related to the timing of treatment initiation among HIV-infected children attending three clinical sites in Uganda. Clinical and demographic determinants associated with early disease (WHO clinical stages 1-2) or late disease (stages 3-4) stage at presentation were assessed using multilevel logistic regression. Additionally, semistructured interviews with caregivers and health workers were conducted to qualitatively explore determinants of late disease stage at presentation. Of 306 children initiating first-line regimens, 72% presented late. Risk factors for late presentation were age below 2 years old (OR 2.83, P=0.014), living without parents (OR 3.93, P=0.002), unemployment of the caregiver (OR 4.26, P=0.001), lack of perinatal HIV prophylaxis (OR 5.66, P=0.028), and high transportation costs to the clinic (OR 2.51, P=0.072). Forty-nine interviews were conducted, confirming the identified risk factors and additionally pointing to inconsistent referral from perinatal care, caregivers' unawareness of HIV symptoms, fear, and stigma as important barriers. The problem of late disease at presentation requires a multifactorial approach, addressing both health system and individual-level factors

HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: A multicentre observational study

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

Mortality and readmission rates among hospitalized COVID-19 patients with varying stages of chronic kidney disease:a multicenter retrospective cohort

Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages. We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort. The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score = 4. A total of 4151 hospitalized COVID-19 patients were included of who 389 had a history of CKD before admission. After adjusting for all confounding covariables, in patients with CKD stage 3a, stage 3b, stage 4 and patients with KTX (kidney transplantation), odds ratios of death and readmission compared to patients without CKD ranged from 1.96 to 8.94. We demonstrate an evident increased 12-week mortality and readmission rate in patients with chronic kidney disease. Besides justified concerns for kidney transplant patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patients