Rates of emergence of HIV drug resistance in resource-limited settings: A systematic review
University of California, San Diego, San Diego, CA, USA. Antiviral therapy
(Impact Factor: 3.02).
10/2012; 18(1). DOI: 10.3851/IMP2437
The increasing availability of antiretroviral therapy (ART) has improved survival and quality of life for many infected with HIV, but can also engender drug resistance. This review summarizes the available information on drug resistance in adults in resource-limited settings.
The online databases PubMed and Google Scholar, pertinent conference abstracts and references from relevant articles were searched for publications available before November 2011. Data collected after ART rollout were reviewed.
A total of 7 studies fulfilled the criteria for the analysis of acquired drug resistance and 22 fulfilled the criteria for the analysis of transmitted drug resistance (TDR). Acquired resistance was detected in 7.2% of patients on ART for 6-11 months, 11.1% at 12-23 months, 15.0% at 24-35 months, and 20.7% at ≥ 36 months. Multi-class drug resistance increased steadily with time on ART. The overall rate of TDR in all resource-limited countries studied was 6.6% (469/7,063). Patients in countries in which ART had been available for ≥ 5 years were 1.7 × more likely to have TDR than those living in a country where ART had been available for <5 years (P<0.001). The reported prevalence of TDR was 5.7% (233/4,069) in Africa, 7.6% (160/2,094) in Asia and 8.4% (76/900) in Brazil.
The emergence of drug resistance following access to ART in resource-limited settings resembles what was seen in resource-rich countries and highlights the need for virological monitoring for drug failure, drug resistance testing and alternative drug regimens that have proven beneficial in these resource-rich settings.
Available from: Giacomo Maria Paganotti
- "subjects show a genotype pattern with 3 variant alleles at position 516 and 983 (516TT/983TC), leading possibly to a further additional reduction of enzyme activity. Thus, they do have very low predictive chance to metabolise well EFV and, to less extent also NVP (Stadeli and Richman, 2013; Micheli et al., 2013), that are the most prescribed ARVs drug in RLCs (WHO, 2013). This phenomenon raises the possibility of increased risk of ARVs adverse events, followed by lower ART compliance and then higher selective pressure for drug resistance selection. "
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ABSTRACT: The prescription of patients' tailored anti-infectious treatments is the ultimate goal of pharmacogenetics/genomics applied to antimicrobial treatments, providing a basis for personalized medicine. Despite the efforts to screen Africans for alleles underlying defective metabolism for a panel of different drugs, still more research is necessary to clarify the interplay between host genetic variation and treatments' response. HIV is a major infectious disease in sub-Saharan African countries, and the main prescribed anti-HIV combination therapy includes efavirenz (EFV) or nevirapine (NVP). The two drugs are both mainly metabolised by cytochrome P450 2B6 liver enzyme (CYP2B6). Defective variants of CYP2B6 gene, leading to higher drug exposure with subsequent possible side effects and low compliance, are well known. However, little is known about CYP2B6 alleles in Cameroon where only one study was done on this subject. The main objective of the present work is to assess, in a subset of HIV-exposed subjects from Dschang in West Cameroon, the prevalence of two SNPs in the CYP2B6 gene: 516G>T (rs3745274) and 983T>C (rs28399499), both associated to a defective EFV and NVP metabolism. We analyzed 168 DNA samples collected during two cross-sectional surveys performed in Dschang, West Cameroon. In the population studied the observed allele frequencies of 516G>T and 983T>C were 44.35% (95%CI, 36.84-51.86%) and 12.80% (95%CI, 7.75-17.85%), respectively. Moreover, concerning the CYP2B6 expected phenotypes, 28.57% of the population showed a poor metaboliser phenotype, while 27.38% and 44.05% showed an extensive (wild-type) and an intermediate metaboliser phenotype, respectively. Here we found that an important fraction of the subjects is carrying EFV/NVP poor metaboliser alleles. Our findings could help to improve the knowledge about the previewed efficacy of anti-HIV drug therapy in Cameroon. Finally, we designed a new method of detection for the 983T>C genetic variation that can be applied in resource-limited laboratories.
Copyright © 2015 Elsevier B.V. All rights reserved.
Infection Genetics and Evolution 08/2015; 35:122-126. DOI:10.1016/j.meegid.2015.08.003 · 3.02 Impact Factor
Available from: Constanze Müller
- "As of August 2012, 23 single-molecule drugs were approved for anti-HIV-1 therapy in the USA by the FDA . The continuous need for the development of new therapeutic anti-HIV-1 agents arises from the rapid emergence of viruses resistant to these drugs (reviewed in , ), the necessity for continuous life-long treatment , the challenges of providing antiretroviral treatment in resource-limited settings  and the need for novel drugs with fewer adverse effects . "
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ABSTRACT: Global HIV-1 treatment would benefit greatly from safe herbal medicines with scientifically validated novel anti-HIV-1 activities. The root extract from the medicinal plant Pelargonium sidoides (PS) is licensed in Germany as the herbal medicine EPs®7630, with numerous clinical trials supporting its safety in humans. Here we provide evidence from multiple cell culture experiments that PS extract displays potent anti-HIV-1 activity. We show that PS extract protects peripheral blood mononuclear cells and macrophages from infection with various X4 and R5 tropic HIV-1 strains, including clinical isolates. Functional studies revealed that the extract from PS has a novel mode-of-action. It interferes directly with viral infectivity and blocks the attachment of HIV-1 particles to target cells, protecting them from virus entry. Analysis of the chemical footprint of anti-HIV activity indicates that HIV-1 inhibition is mediated by multiple polyphenolic compounds with low cytotoxicity and can be separated from other extract components with higher cytotoxicity. Based on our data and its excellent safety profile, we propose that PS extract represents a lead candidate for the development of a scientifically validated herbal medicine for anti-HIV-1 therapy with a mode-of-action different from and complementary to current single-molecule drugs.
PLoS ONE 01/2014; 9(1):e87487. DOI:10.1371/journal.pone.0087487 · 3.23 Impact Factor
Available from: Tobias Floris Rinke de Wit
- "A systematic review of virological efficacy and drug resistance outcomes of patients on ART programmes in sSA has reported 76% virological suppression after 12 months on ART and 67% after 24 months . Similarly, a recent systematic review from resource limited settings report HIV drug resistance of 11% in patients on ART for 12–23 months, 15% at 24–36 months and 21% at >36 months . The most common resistance profiles identified include the M184V mutation (associated with nucleoside reverse transcriptase inhibitors; NRTIs), followed by the K103N mutation (associated with non-nucleoside reverse transcriptase inhibitors; NNRTIs). "
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ABSTRACT: An increasing number of people on antiretroviral therapy (ART) in sub-Saharan Africa has led to declines in HIV related morbidity and mortality. However, virologic failure (VF) and acquired drug resistance (ADR) may negatively affect these gains. This study describes the prevalence and correlates of HIV-1 VF and ADR among first-line ART experienced adults at a rural HIV clinic in Coastal Kenya.
HIV-infected adults on first-line ART for >=6 months were cross-sectionally recruited between November 2008 and March 2011. The primary outcome was VF, defined as a one-off plasma viral load of >=400 copies/ml. The secondary outcome was ADR, defined as the presence of resistance associated mutations. Logistic regression and Fishers exact test were used to describe correlates of VF and ADR respectively.
Of the 232 eligible participants on ART over a median duration of 13.9 months, 57 (24.6% [95% CI: 19.2 - 30.6]) had VF. Fifty-five viraemic samples were successfully amplified and sequenced. Of these, 29 (52.7% [95% CI: 38.8 - 66.3]) had at least one ADR, with 25 samples having dual-class resistance mutations. The most prevalent ADR mutations were the M184V (n = 24), K103N/S (n = 14) and Y181C/Y/I/V (n = 8). Twenty-six of the 55 successfully amplified viraemic samples (47.3%) did not have any detectable resistance mutation. Younger age (15-34 vs. >=35 years: adjusted odd ratios [95% CI], p-value: 0.3 [0.1-0.6], p = 0.002) and unsatisfactory adherence (<95% vs. >=95%: 3.0 [1.5-6.5], p = 0.003) were strong correlates of VF. Younger age, unsatisfactory adherence and high viral load were also strong correlates of ADR.
High levels of VF and ADR were observed in younger patients and those with unsatisfactory adherence. Youth-friendly ART initiatives and strengthened adherence support should be prioritized in this Coastal Kenyan setting. To prevent unnecessary/premature switches, targeted HIV drug resistance testing for patients with confirmed VF should be considered.
AIDS Research and Therapy 01/2014; 11(1):9. DOI:10.1186/1742-6405-11-9 · 1.46 Impact Factor
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