Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: A global collaborative study and meta-regression analysis

Department of Infection, University College London, London, UK.
The Lancet (Impact Factor: 45.22). 07/2012; 380(9849):1250-8. DOI: 10.1016/S0140-6736(12)61038-1
Source: PubMed


The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings.
We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models.
Study-level data were available for 26,102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (-0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region.
Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries--no changes in antiretroviral treatment guidelines are warranted at the moment.
Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme.

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    • "The two fold variation in the magnitude of drug resistance between IAS drug resistance mutations lists (13.1%) and HIVDB DR Interpretation algorithm (5.6%) indicates the difficulty of interpreting drug resistance mutation in subtype C isolates [16-20]. The level of drug resistance in the current study is significantly higher than the previous report from the same area (3.3%) sampled in 2002 [7] but similar with findings from other eastern and southern Africa countries after the roll out of ART [4-6] which support the notion that scaling up of ART in Africa will drive the emergence of TDR. The findings also imply that many HIV infected individuals receiving ART are continuing to exercise risk related behaviour which is in line with behavioural study in Ethiopia [21] and an eventual increase of TDR cases is anticipated in the country. "
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    ABSTRACT: Despite the increasing use of antiretroviral treatment (ART) recent data on frequency and pattern of drug resistance mutations in Ethiopia is not available. Furthermore with increasing mobility of people HIV-1 subtypes other than the predominant subtype C may likely be introduced from the neighbouring countries. This study was aimed to determine the molecular characterization and pre-antiretroviral treatment resistance mutations among HIV-1 chronically infected ART naive patients after the roll out of ART in Ethiopia. Viral RNA was determined in 160 baseline plasma samples. The entire PR and the first 335 codons (76%) of the RT regions of the pol gene of the HIV-1 genome (N = 160) were amplified and sequenced using an in-house assay. Genotypic drug resistance was defined as the presence of one or more resistance-related mutations as specified by the consensus mutation of Stanford University HIVDB and the International Antiviral Society (IAS) mutation lists. A predominance of HIV-1 subtype C (98.7%) was observed. The level of drug resistance is found to be 5.0% and 12.5% according to the Stanford University HIVDB drug resistance interpretation algorithms and the International Antiviral Society mutation lists, respectively. Mutations conferring simultaneous resistance to NRTIs and NNRTIs were not detected and no major PR mutation was found. However, a high rate of polymorphic changes both in PR and RT regions were observed. Moreover, twenty four (15%) monophyletic transmission clusters with bootstrap value of 99% were found. Strong evidence for consistent HIV-1C clade homogeneity and low influx of other variant into the country was found. The level of drug resistance observed in chronically infected treatment naive patients which exceeds the WHO estimates suggests the need for incorporation of HIV-1 drug resistance testing prior to ART initiation. The occurrence of monophyletic transmission clusters affecting (24/160) individuals indicates their potential risk related practice. Thus, an intensified public health intervention program and monitoring of HIV drug resistance testing appears indispensible.
    BMC Infectious Diseases 03/2014; 14(1):158. DOI:10.1186/1471-2334-14-158 · 2.61 Impact Factor
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    • "With good compliance to current first-line combination drug regimens, resistance is less common but remains a concern in settings where the drugs or drug combinations used and/or patient compliance are not optimal [1]–[3]. In addition to posing a significant clinical challenge, particularly in resource-limited settings [4], [5], transmission of drug-resistant virus could complicate control of the HIV pandemic [2], [6]–[9]. Prophylactic strategies such as Pre-Exposure Prophylaxis (PrEP) and microbicides, which are targeted toward HIV-uninfected individuals, could potentially be used by infected persons, some of whom are unaware of their HIV status [10], thereby enhancing the selection and transmission of drug-resistant HIV [11]. "
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    ABSTRACT: When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.
    PLoS ONE 02/2014; 9(2):e89300. DOI:10.1371/journal.pone.0089300 · 3.23 Impact Factor
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    • "Up to now, there are no effective drugs and therapies for complete cure of AIDS. Extensive application of ART has greatly reduced the morbidity and mortality of HIV/AIDS patients [4]–[6]. "
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    ABSTRACT: Natural drug resistance is a major cause of antiviral treatment failure. The characteristics of HIV-1 natural drug resistance-associated mutations in former paid blood donors in Henan Province remain unclear. One hundred and fifty HIV-1-positive plasma samples were collected. Plasma viral RNA was extracted for pol gene amplification and sequencing. The sequencing results were submitted to the HIV-1 drug resistance database for drug-resistance analysis. The rates of natural drug resistance and resistance-associated mutations were 17.7% (19/107) and 40.2% (43/107), respectively. The rates of PI major, PI minor, NRTI, and NNRTI mutations were: 0, 30.8% (33/107), 10.3% (11/107), and 18.7% (20/107), respectively. Nine cases (8.4%) had both NRTI and NNRTI resistance-associated mutations. Seven cases (6.5%) had PI minor, NRTI and NNRTI resistance-associated mutations. NNRTI resistance was the most serious, followed by NRTI resistance and PI resistance. Polymorphism mutation sites with mutation rates in the protease region higher than 60.0% were: L63A/P/S/T 89.7%, V77I 82.2%, I72E/M/K/T/V 80.4%, I93L 75.7%, and E35D 72.9%. Polymorphism mutation sites with mutation rates in the RT region higher than 60.0% were: I135A/L/M/R/T/V 93.5%, T200A/E/I/P/V 89.7%, Q278E/K/N/T 88.8%, S162C/Y 82.2%, and K277R/S 66.4%. The distribution of 107 gene sequences was scattered, with some drug-resistant strains grouped in the same cluster. The natural drug resistance mutation rate of HIV-1 in former paid blood donors in Henan Province was 17.7%, with NNRTI resistance the most serious. The distribution of drug-resistant strains was scattered, with some correlations found in certain resistance loci.
    PLoS ONE 02/2014; 9(2):e89291. DOI:10.1371/journal.pone.0089291 · 3.23 Impact Factor
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