World Health Organization Generic Protocol to Assess Drug-Resistant HIV Among Children <18 Months of Age and Newly Diagnosed With HIV in Resource-Limited Countries

Increased use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in pregnant and breastfeeding women will result in fewer children infected with human immunodeficiency virus (HIV). However, among children infected despite prevention of mother-to-child transmission (PMTCT), a substantial proportion will acquire NNRTI-resistant HIV, potentially compromising response to NNRTI-based antiretroviral therapy (ART). In countries scaling up PMTCT and pediatric ART programs, it is crucial to assess the proportion of young children with drug-resistant HIV to improve health outcomes and support national and global decision making on optimal selection of pediatric first-line ART. This article summarizes a new World Health Organization surveillance protocol to assess resistance using remnant dried blood spot specimens from a representative sample of children aged <18 months being tested for early infant diagnosi

Drivers of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in nine southern African countries: a modelling study.

INTRODUCTION: The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance. METHODS: We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country. RESULTS: The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9-7.1) in Mozambique and 25.3% (17.9-33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2-14) in Eswatini to 64% (26-85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0-0.11) but high in Namibia (0.48; 0.16-10.17), Eswatini (0.64; 0.23-11.8) and South Africa (1.21; 0.83-9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance. CONCLUSIONS: This comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART

Impact of HIV drug resistance on HIV/AIDS associated mortality, new infections and antiretroviral therapy program costs in sub-Saharan Africa

To inform the level of attention to be given by antiretroviral therapy (ART) programs to HIV drug resistance (HIVDR), we used an individual-level model to estimate its impact on future AIDS deaths, HIV-incidence and ART program costs in sub-Saharan Africa (SSA) for a range of program situations. We applied this to SSA through the Spectrum-Goals model. In a situation in which current levels of pre-treatment HIVDR are over 10% (mean 15%), 16% of AIDS deaths (890,000 deaths) , 9% of new infections (450,000) and 8% ($6.5 billion) of ART program costs in SSA in 2016-2030 will be attributable to HIVDR

HIV Drug Resistance Early Warning Indicators in Cohorts of Individuals Starting Antiretroviral Therapy Between 2004 and 2009: World Health Organization Global Report From 50 Countries

The World Health Organization developed a set of human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) to assess antiretroviral therapy clinic and program factors associated with HIVDR. EWIs are monitored by abstracting data routinely recorded in clinical records, and the results enable clinics and program managers to identify problems that should be addressed to minimize preventable emergence of HIVDR in clinic populations. As of June 2011, 50 countries monitored EWIs, covering 131 686 patients initiating antiretroviral treatment between 2004 and 2009 at 2107 clinics. HIVDR prevention is associated with patient care (appropriate prescribing and patient monitoring), patient behavior (adherence), and clinic/program management efforts to reduce treatment interruptions (follow up, retention on first-line ART, procurement and supply management of antiretroviral drugs). EWIs measure these factors and the results have been used to optimize patient and population treatment outcome

Surveillance of Transmitted Drug-Resistant HIV Among Young Pregnant Women in Ouagadougou, Burkina Faso

Burkina Faso began rapid antiretroviral therapy (ART) scale-up in 2003 and by December 2009, 26 448 individuals were on treatment. With rapid scale-up of ART, some degree of human immunodeficiency virus transmitted drug resistance (TDR) is inevitable. Following World Health Organization methods, between June 2008 and July 2009, Burkina Faso assessed TDR in primigravid pregnant women aged <25 years attending antenatal care clinics in Ouagadougou, Burkina Faso. TDR was classified as moderate (5%-15%) for both nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors. The observed moderate TDR in Ouagadougou is a cause for concern and calls for closer monitoring of Burkina Faso's ART progra

Pharmacy Adherence Measures to Assess Adherence to Antiretroviral Therapy: Review of the Literature and Implications for Treatment Monitoring

Prescription or pill-based methods for estimating adherence to antiretroviral therapy (ART), pharmacy adherence measures (PAMs), are objective estimates calculated from routinely collected pharmacy data. We conducted a literature review to evaluate PAMs, including their association with virological and other clinical outcomes, their efficacy compared with other adherence measures, and factors to consider when selecting a PAM to monitor adherence. PAMs were classified into 3 categories: medication possession ratio (MPR), pill count (PC), and pill pick-up (PPU). Data exist to recommend PAMs over self-reported adherence. PAMs consistently predicted patient outcomes, but additional studies are needed to determine the most predictive PAM parameters. Current evidence suggests that shorter duration of adherence assessment (≤6 months) and use of PAMs to predict future outcomes may be less accurate. PAMs which incorporate the number of days for which ART was prescribed without the counting of remnant pills, are reasonable minimum-resource methods to assess adherence to AR

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial.

BACKGROUND: Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV. METHODS: We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12-16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039). FINDINGS: Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004). INTERPRETATION: Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck

High levels of resistance to nucleoside/nucleotide reverse transcriptase inhibitors in newly diagnosed antiretroviral treatment-naive children in sub-Saharan Africa.

: Exposure of infants to antiretroviral drugs for prevention of mother-to-child transmission can induce resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Data from nine national surveys of pretreatment drug resistance in children newly diagnosed with HIV show high levels of resistance to NRTIs included in first-line antiretroviral treatment (ART) regimens (dual abacavir-lamivudine/emtricitabine resistance). Additional research is needed to determine the impact of NRTI resistance on treatment response and optimize infant ART