Prevalence and Correlates of Viral Load Suppression and Human Immunodeficiency Virus (HIV) Drug Resistance Among Children and Adolescents in South Rift Valley and Kisumu, Kenya.

BACKGROUND: Children and adolescents living with HIV (CALHIV) face unique challenges, including poorer treatment outcomes, risk for drug-resistance mutations (HIVDRMs), and limited drug formulations. We estimated viral suppression (VS) prevalence and evaluated predictors of VS and HIVDRMs in Kenya. METHODS: From 2018-2020, CALHIV 1-19 years on antiretroviral therapy (ART) >6 months were enrolled in this cross-sectional study. Participants underwent viral load (VL) testing; those with VL ≥1000 copies/mL had HIVDRM testing. Sociodemographic questionnaires and medical record abstraction were completed. VS prevalence (VL <1000 copies/mL) was estimated; robust Poisson regression models were used to estimate prevalence ratios (PRs) and 95% CIs for associations between potential predictors of VS. RESULTS: Nine hundred and sixty-nine participants were enrolled. VS prevalence was .80 (95% CI: .78-.83). Being on ART >24 months (adjusted PR [aPR]: 1.22; 95% CI: 1.06-1.41), an integrase strand transfer inhibitor-containing regimen (1.13; 1.02-1.26), and attending a level 3 health facility (1.23; 1.11-1.36) were associated with VS. Missing ≥3 doses of ART in the past month (aPR: .73; 95% CI: .58-.92), having a viremic mother with HIV (.72; .53-.98), and having 3-7 (.90; .83-.97), 8-13 (.89; .82-.97), or ≥14 (.84; .77-.92) compared with <2 adherence counseling referrals were inversely associated with VS. A high proportion (n = 119, 81.5%) of unsuppressed participants had evidence of any major HIVDRM. CONCLUSIONS: HIV treatment programs should target interventions for pediatric patients at risk for treatment failure-namely, those with a caregiver with failed VS and those struggling with adherence.

Pretreatment and Acquired Antiretroviral Drug Resistance Among Persons Living With HIV in Four African Countries.

BACKGROUND: Emerging HIV drug resistance (HIVDR) could jeopardize the success of standardized HIV management protocols in resource-limited settings. We characterized HIVDR among antiretroviral therapy (ART)-naive and experienced participants in the African Cohort Study (AFRICOS). METHODS: From January 2013 to April 2019, adults with HIV-1 RNA >1000 copies/mL underwent ART history review and HIVDR testing upon enrollment at 12 clinics in Uganda, Kenya, Tanzania, and Nigeria. We calculated resistance scores for specific drugs and tallied major mutations to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) using Stanford HIVDB 8.8 and SmartGene IDNS software. For ART-naive participants, World Health Organization surveillance drug resistance mutations (SDRMs) were noted. RESULTS: HIVDR testing was performed on 972 participants with median age 35.7 (interquartile range [IQR] 29.7-42.7) years and median CD4 295 (IQR 148-478) cells/mm3. Among 801 ART-naive participants, the prevalence of SDRMs was 11.0%, NNRTI mutations 8.2%, NRTI mutations 4.7%, and PI mutations 0.4%. Among 171 viremic ART-experienced participants, NNRTI mutation prevalence was 83.6%, NRTI 67.8%, and PI 1.8%. There were 90 ART-experienced participants with resistance to both efavirenz and lamivudine, 33 (36.7%) of whom were still prescribed these drugs. There were 10 with resistance to both tenofovir and lamivudine, 8 (80.0%) of whom were prescribed these drugs. CONCLUSIONS: Participants on failing ART regimens had a high burden of HIVDR that potentially limited the efficacy of standardized first- and second-line regimens. Management strategies that emphasize adherence counseling while delaying ART switch may promote drug resistance and should be reconsidered.

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans.

APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

Field evaluation of a broadly sensitive HIV-1 in-house genotyping assay for use with both plasma and dried blood spot specimens in a resource-limited country.

HIV-1 drug resistance (HIVDR) assays are important tools in clinical management of HIV-infected patients on antiretroviral therapy (ART) and surveillance of drug-resistant variants at population levels. The high cost associated with commercial assays hinders their use in resource-limited settings. We adopted and validated a low-cost in-house assay using 68 matched plasma and dried blood spot (DBS) samples with a median viral load (VL) of 58,187 copies/ml, ranging from 253 to 3,264,850 against the commercial assay ViroSeq. Results indicated that the in-house assay not only had a higher plasma genotyping rate than did ViroSeq (94% versus 78%) but also was able to genotype 89.5% (51/57) of the matched DBS samples with VLs of ≥ 1,000 copies/ml. The sensitivity in detecting DR mutations by the in-house assay was 98.29% (95% confidence interval [CI], 97.86 to 98.72) on plasma and 96.54 (95% CI, 95.93 to 97.15) on DBS, and the specificity was 99.97% (95% CI, 99.91 to 100.00) for both sample types compared to ViroSeq. The minor DR mutation differences detected by the in-house assay against ViroSeq did not result in clinical significance. In addition, cost analysis showed that the in-house assay could reduce the genotyping cost by about 60% for both plasma and DBS compared to ViroSeq. This field condition evaluation highlights the potential utility of a cost-effective, subtype-independent, in-house genotyping assay using both plasma and DBS specimens for HIVDR clinical monitoring and population-based surveillance in resource-limited settings.

Molecular Epidemiology and Transmission Dynamics of Recent and Long-Term HIV-1 Infections in Rural Western Kenya.

OBJECTIVE: To identify unique characteristics of recent versus established HIV infections and describe sexual transmission networks, we characterized circulating HIV-1 strains from two randomly selected populations of ART-naïve participants in rural western Kenya. METHODS: Recent HIV infections were identified by the HIV-1 subtype B, E and D, immunoglobulin G capture immunoassay (IgG BED-CEIA) and BioRad avidity assays. Genotypic and phylogenetic analyses were performed on the pol gene to identify transmitted drug resistance (TDR) mutations, characterize HIV subtypes and potential transmission clusters. Factors associated with recent infection and clustering were assessed by logistic regression. RESULTS: Of the 320 specimens, 40 (12.5%) were concordantly identified by the two assays as recent infections. Factors independently associated with being recently infected were age ≤19 years (P = 0.001) and history of sexually transmitted infections (STIs) in the past six months (P = 0.004). HIV subtype distribution differed in recently versus chronically infected participants, with subtype A observed among 53% recent vs. 68% chronic infections (p = 0.04) and subtype D among 26% recent vs. 12% chronic infections (p = 0.012). Overall, the prevalence of primary drug resistance was 1.16%. Of the 258 sequences, 11.2% were in monophyletic clusters of between 2-4 individuals. In multivariate analysis factors associated with clustering included having recent HIV infection P = 0.043 and being from Gem region P = 0.002. CONCLUSIONS: Recent HIV-1 infection was more frequent among 13-19 year olds compared with older age groups, underscoring the ongoing risk and susceptibility of younger persons for acquiring HIV infection. Our findings also provide evidence of sexual networks. The association of recent infections with clustering suggests that early infections may be contributing significant proportions of onward transmission highlighting the need for early diagnosis and treatment as prevention for ongoing prevention. Larger studies are needed to better understand the structure of these networks and subsequently implement and evaluate targeted interventions.

African origins and chronic kidney disease susceptibility in the human immunodeficiency virus era.

Chronic kidney disease (CKD) is a major public health problem worldwide with the estimated incidence growing by approximately 6% annually. There are striking ethnic differences in the prevalence of CKD such that, in the United States, African Americans have the highest prevalence of CKD, four times the incidence of end stage renal disease when compared to Americans of European ancestry suggestive of genetic predisposition. Diabetes mellitus, hypertension and human immunodeficiency virus (HIV) infection are the major causes of CKD. HIV-associated nephropathy (HIVAN) is an irreversible form of CKD with considerable morbidity and mortality and is present predominantly in people of African ancestry. The APOL1 G1 and G2 alleles were more strongly associated with the risk for CKD than the previously examined MYH9 E1 risk haplotype in individuals of African ancestry. A strong association was reported in HIVAN, suggesting that 50% of African Americans with two APOL1 risk alleles, if untreated, would develop HIVAN. However these two variants are not enough to cause disease. The prevailing belief is that modifying factors or second hits (including genetic hits) underlie the pathogenesis of kidney disease. This work reviews the history of genetic susceptibility of CKD and outlines current theories regarding the role for APOL1 in CKD in the HIV era.