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Journal ArticleDOI

Extraordinary Heterogeneity of Virological Outcomes in Patients Receiving Highly Antiretroviral Therapy and Monitored With the World Health Organization Public Health Approach in Sub-Saharan Africa and Southeast Asia

TL;DR: The findings show heterogeneous virological failure and illustrate that, in addition to routine access to viral load, good management of ART programs is even more critical to improve treatment outcomes in resource-limited countries.
Abstract: Background The limited access to virological monitoring in developing countries is a major weakness of the current antiretroviral treatment (ART) strategy in these settings. We conducted a large cross-sectional study in Burkina Faso, Cameroon, Cote d'Ivoire, Senegal, Togo, Thailand, and Vietnam to assess virological failure and drug resistance mutations (DRMs) after 12 or 24 months of ART. Methods Between 2009 and 2011, we recruited adults attending ART centers 10-14 months (the M12 group) or 22-26 months (M24 group) after initiating ART. Demographic and clinical data were collected on site, and viral load was measured. Samples with a viral load of ≥ 1000 copies/mL, considered as the failure threshold, were genotyped for drug resistance assessment. Results Overall, 3935 patients were recruited (2060 at M12 and 1875 at M24). Median ages varied from 32 to 42 years. Median CD4(+) T-cell counts at ART initiation were low (99-172 cells/µL). The main ART regimens included stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. Overall, virological failure frequency was 11.1% for M12 patients and 12.4% for M24 patients, and 71.0% to 86.1% of these patients, respectively, had drug-resistant virus. Across sites, virological failure varied from 2.9% to 20.6% in M12 patients and from 3.7% to 26.0% in M24 patients. Predominant DRMs were associated with ART regimens, but virus in several patients accumulated DRMs to drugs not received, such as abacavir, didanosine, tenofovir, etravirine, and rilpivirine. Conclusions Our findings show heterogeneous virological failure and illustrate that, in addition to routine access to viral load, good management of ART programs is even more critical to improve treatment outcomes in resource-limited countries.
Citations
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Journal ArticleDOI
TL;DR: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains.
Abstract: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naive individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

206 citations

Journal ArticleDOI
24 Oct 2014-BMJ
TL;DR: No significant effect of the mobile phone intervention on either time to virological failure or ART adherence at the end of two years of therapy is found in this multicentre randomised controlled trial among HIV infected patients starting antiretroviral treatment.
Abstract: Objective To assess whether customised mobile phone reminders would improve adherence to therapy and thus decrease virological failure among HIV infected patients starting antiretroviral treatment (ART). Design Randomised controlled trial among HIV infected patients initiating antiretroviral treatment. Setting Three diverse healthcare delivery settings in south India: two ambulatory clinics within the Indian national programme and one private HIV healthcare clinic. Participants 631 HIV infected, ART naive, adult patients eligible to initiate first line ART were randomly assigned to mobile phone intervention (n=315) or standard care (n=316) and followed for 96 weeks.. Intervention The intervention consisted of customised, interactive, automated voice reminders, and a pictorial message that were sent weekly to the patients’ mobile phones for the duration of the study. Main outcome measures The primary outcome was time to virological failure (viral load >400 copies/mL on two consecutive measurements). Secondary outcomes included ART adherence measured by pill count, death rate, and attrition rate. Suboptimal adherence was defined as mean adherence <95%. Results Using an intention-to-treat approach we found no observed difference in time to virological failure between the allocation groups: failures in the intervention and standard care arms were 49/315 (15.6%) and 49/316 (15.5%) respectively (unadjusted hazard ratio 0.98, 95% confidence interval 0.67 to 1.47, P=0.95). The rate of virological failure in the intervention and standard care groups were 10.52 and 10.73 per 100 person years respectively. Comparison of suboptimal adherence was similar between both groups (unadjusted incidence rate ratio 1.24, 95% CI 0.93 to 1.65, P=0.14). Incidence proportion of patients with suboptimal adherence was 81/300 (27.0%) in the intervention arm and 65/299 (21.7%) in the standard care arm. The results of analyses adjusted for potential confounders were similar, indicating no significant difference between the allocation groups. Other secondary outcomes such as death and attrition rates, and subgroup analysis also showed comparable results across allocation groups. Conclusions In this multicentre randomised controlled trial among ART naive patients initiating first line ART within the Indian national programme, we found no significant effect of the mobile phone intervention on either time to virological failure or ART adherence at the end of two years of therapy. Trial registration Current Controlled Trials [ISRCTN79261738][1]. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN79261738

91 citations

Journal ArticleDOI
30 Dec 2015-PLOS ONE
TL;DR: This study proposes that two major nucleoside reverse transcriptase inhibitor (N RTI)-associated DRMs and four major NNRTI-associated DRs would be the most useful for POC genotypic resistance testing in LMIC settings.
Abstract: The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naive individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naive individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.

76 citations

Journal ArticleDOI
TL;DR: DBS can be successfully used as an alternative to blood plasma samples for routine VL and HIVDR monitoring in African and Asian settings, however, the selection of an adequate VL measurement method and the definition of the VF threshold should be considered, and laboratory performance should be monitored.
Abstract: Dried blood spots (DBS) can be used in developing countries to alleviate the logistic constraints of using blood plasma specimens for viral load (VL) and HIV drug resistance (HIVDR) testing, but they should be assessed under field conditions. Between 2009 and 2011, we collected paired plasma-DBS samples from treatment-experienced HIV-1-infected adults in Burkina Faso, Cameroon, Senegal, Togo, Thailand, and Vietnam. The DBS were stored at an ambient temperature for 2 to 4 weeks and subsequently at -20°C before testing. VL testing was performed on the plasma samples and DBS using locally available methods: the Abbott m2000rt HIV-1 test, generic G2 real-time PCR, or the NucliSENS EasyQ version 1.2 test. In the case of virological failure (VF), i.e., a plasma VL of ≥1,000 copies/ml, HIVDR genotyping was performed on paired plasma-DBS samples. Overall, we compared 382 plasma-DBS sample pairs for DBS VL testing accuracy. The sensitivities of the different assays in different laboratories for detecting VF using DBS varied from 75% to 100% for the m2000rt test in labs B, C, and D, 91% to 93% for generic G2 real-time PCR in labs A and F, and 85% for the NucliSENS test in lab E. The specificities varied from 82% to 97% for the m2000rt and NucliSENS tests and reached only 60% for the generic G2 test. The NucliSENS test showed good agreement between plasma and DBS VL but underestimated the DBS VL. The lowest agreement was observed for the generic G2 test. Genotyping was successful for 96/124 (77%) DBS tested, and 75/96 (78%) plasma-DBS pairs had identical HIVDR mutations. Significant discrepancies in resistance interpretations were observed in 9 cases, 6 of which were from the same laboratory. DBS can be successfully used as an alternative to blood plasma samples for routine VL and HIVDR monitoring in African and Asian settings. However, the selection of an adequate VL measurement method and the definition of the VF threshold should be considered, and laboratory performance should be monitored.

62 citations

Journal ArticleDOI
05 Feb 2019-PLOS ONE
TL;DR: It is shown that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART, and being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virology failure.
Abstract: Introduction The 2016 WHO consolidated guidelines on the use of antiretroviral drugs defines HIV virologic failure for low and middle income countries (LMIC) as plasma HIV-RNA ≥ 1000 copies/mL. We evaluated virologic failure and predictors in four African countries. Materials and methods We included HIV-infected participants on a WHO recommended antiretroviral therapy (ART) regimen and enrolled in the African Cohort Study between January 2013 and October 2017. Studied outcomes were virologic failure (plasma HIV-RNA ≥ 1000 copies/mL at the most recent visit), viraemia (plasma HIV-RNA ≥ 50 copies/mL at the most recent visit); and persistent viraemia (plasma HIV-RNA ≥ 50 copies/mL at two consecutive visits). Generalized linear models were used to estimate relative risks with their 95% confidence intervals. Results 2054 participants were included in this analysis. Viraemia, persistent viraemia and virologic failure were observed in 396 (19.3%), 160 (7.8%) and 184 (9%) participants respectively. Of the participants with persistent viraemia, only 57.5% (92/160) had confirmed virologic failure. In the multivariate analysis, attending clinical care site other than the Uganda sitebeing on 2nd line ART (aRR 1.8, 95% CI 1·28–2·66); other ART combinations not first line and not second line (aRR 3.8, 95% CI 1.18–11.9), a history of fever in the past week (aRR 3.7, 95% CI 1.69–8.05), low CD4 count (aRR 6.9, 95% CI 4.7–10.2) and missing any day of ART (aRR 1·8, 95% CI 1·27–2.57) increased the risk of virologic failure. Being on 2nd line therapy, the site where one receives care and CD4 count < 500 predicted viraemia, persistent viraemia and virologic failure. Conclusion In conclusion, these findings demonstrate that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART. The findings also show that being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virologic failure that should trigger intensified adherence counselling especially in the absence of reliable or readily available viral load monitoring. Finally, clinical care sites are different calling for further analyses to elucidate on the unique features of these sites.

55 citations

References
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01 Jan 2006
TL;DR: These guidelines are primarily intended for use by national and regional HIV programme managers managers of nongovernmental organizations delivering HIV care services and other policy-makers who are involved in the scaling up of comprehensive HIV care and ART in resource-limited countries.
Abstract: This publication is intended to serve as a reference tool for countries with limited resources as they develop or revise national guidelines for the use of ART in adults and postpubertal adolescents (see Annex 9 for pubertal Tanner staging; prepubertal adolescents should follow the WHO paediatric guidelines). The material presented takes updated evidence into account including new ART treatment options and draws on the experience of established ART scale-up programmes. The simplified approach with evidence-based standards continues to be the basis of WHO recommendations for the initiation and monitoring of ART. The guidelines are primarily intended for use by national and regional HIV programme managers managers of nongovernmental organizations delivering HIV care services and other policy-makers who are involved in the scaling up of comprehensive HIV care and ART in resource-limited countries. The comprehensive up-to-date technical and clinical information on the use of ART however also makes these guidelines useful for clinicians in resource-limited settings. The recommendations contained in these guidelines are made on the basis of different levels of evidence from randomized clinical trials high-quality scientific studies observational cohort data and where insufficient evidence is available expert opinion. The strengths of the recommendations in Table 1 are intended to indicate the degrees to which the recommendations should be considered by regional and country programmes. Cost-effectiveness is not explicitly considered as part of the recommendations although the realities of human resources health system infrastructures and socioeconomic issues should be taken into account when the recommendations are being adapted to regional and country programmes. (excerpt)

1,454 citations

Journal ArticleDOI
TL;DR: A public-health approach to antiretroviral therapy (ART) to enable scaling-up access to treatment for HIV-positive people in developing countries, recognising that the western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-poor settings.

674 citations


"Extraordinary Heterogeneity of Viro..." refers background in this paper

  • ...Almost all low- and middle-income countries have adopted the WHO public health approach [2, 3] as the standard for antiretroviral (ARV) delivery and monitoring, although doubts exist about the long-term efficacy of this simplified strategy, which has several caveats, compared with the reference approach used in resource-rich countries....

    [...]

Journal ArticleDOI
TL;DR: A significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa is suggested; this rise is driven by NNRTI resistance in studies from east and southern Africa.

356 citations

Journal ArticleDOI
TL;DR: The findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.

314 citations


"Extraordinary Heterogeneity of Viro..." refers result in this paper

  • ...Early results from ART programs in developing countries have been promising, showing virological outcomes similar to those obtained in industrialized settings [4, 5]....

    [...]

Journal ArticleDOI
TL;DR: Reports from resource-limited countries suggest that initial ART programmes are as effective as in resource-rich countries, which should limit HIV drug resistance if programme effectiveness continues during scale-up.
Abstract: Darunavir (TMC114) is a new HIV protease inhibitor that has demonstrated substantial antiretroviral activity against wild-type HIV-1 virus and multidrug-resistant strains Darunavir inhibits and is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes and is coadministered with low-dose ritonavir (darunavir/r); ritonavir is an inhibitor of CYP3A isoenzymes and pharmacologically enhances darunavir, resulting in increased plasma concentrations and allowing for a lower daily dose The t1/2 (terminal elimination half-life) of darunavir is 15 h in the presence of ritonavir An extensive darunavir/r drug-drug interaction programme has been undertaken, covering a wide range of therapeutic areas Studies conducted in HIV-negative healthy volunteers and in HIV-infected patients show that the potential for interactions is well characterized and the interactions are manageable For most drugs investigated, no dose adjustments of darunavir/r or the co-administered drug are required This article reviews all the pharmacokinetic and drug-drug interaction studies conducted to date for darunavir/r, providing guidance on how to co-administer darunavir/r with many other antiretroviral or non-antiretroviral medications commonly used in HIV-infected individuals

305 citations

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