Sub-Saharan Africa continues to have the highest burden of HIV/AIDS worldwide . In response, the WHO-recommended public health approach to antiretroviral therapy (ART) has been widely implemented . This includes standard ART regimens based on first-line nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and ritonavir-boosted protease inhibitors (bPIs) as second-line . Obstacles to full ART access in Africa include weak ART programme functioning, lack of long-term funding and inadequate human resources. A consequence of ART scale-up is treatment failure that selects for drug-resistant HIV-1 (acquired drug resistance). Such virus has the potential to limit the response to subsequent treatment and can be transmitted to newly infected individuals (transmitted drug resistance, TDR). Factors contributing to acquired drug resistance in Africa include the lack of plasma viral load monitoring [4▪], treatment interruptions due to drug stockouts , drug interactions  and the use of substandard antiretroviral regimens [7▪]. These are leading to the concern of drug-resistance and becoming a potential threat to the worldwide control of HIV/AIDS . This review provides an update of the latest data on acquired and transmitted HIV-1 drug resistance in sub-Saharan Africa after the ART scale-up and discusses public health implications.
TRANSMITTED DRUG RESISTANCE
To date, the WHO has reported 44 surveys in recently infected populations from 18 African countries, which suggest that the prevalence of TDR has increased between 2004 and 2010, driven primarily by NNRTI resistance [9▪▪]. Recent local surveys document moderate (5–15%) levels of TDR in Ouagadougou, Burkina Faso , KwaZulu-Natal, South Africa , Kampala, Uganda  and Mombasa, Kenya .
A challenge of TDR surveys is to identify persons who have been recently infected with HIV. A practical alternative is to study HIV-infected persons at the time of ART initiation. The PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort study among 2436 antiretroviral-naive individuals in 11 geographic areas in Kenya, Nigeria, South Africa, Uganda, Zambia and Zimbabwe reported overall baseline prevalence of drug resistance mutations (DRMs) of 5.6% [95% confidence interval (CI) 4.6–6.7] in 2007–2009 [14▪▪]. Drug class-specific resistance prevalence was 2.5% for NRTIs, 3.3% for NNRTIs, 1.3% for bPIs and 1.2% for dual-class resistance to NRTIs and NNRTIs. The most common DRMs were K103N (1.8%), thymidine analogue mutations (TAMs) (1.6%) and M184V (1.2%). Particularly high resistance levels were observed in Uganda (pooled estimate 11.6%), where antiretrovirals were introduced well ahead of nearby countries. PASER-M estimated a 38% increase of the average rate of resistance per year since ART roll-out [14▪▪]. Another study [15▪] in Yaoundé, Cameroon, demonstrated an increasing prevalence of DRMs in antiretroviral-naive persons over time, that is 0.0% in 1996–1999, 1.9% in 2001, 4.1% in 2002 and 12.3% in 2007.
Recently, a comprehensive global assessment of published studies and WHO surveys was performed on HIV-1 drug resistance in untreated patients, including 26 102 persons in 42 countries [16▪▪]. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15–45; P = 0.0001) since roll-out, with an estimated resistance prevalence at 8 years after roll-out of 7.4% (4.3–12.7). An annual increase of 14% (95% CI 0–29; P = 0.054) was estimated in southern Africa, and a nonsignificant increase of 3% (95% CI −0.9 to 16; P = 0.618) in west and central Africa. NNRTI resistance increased substantially in east Africa [36% per year (95% CI 21–52); P < 0.0001] and southern Africa [23% per year (95% CI 7–42); P = 0.0049]. The prevalence of TAMs also seemed to increase in East Africa [31% per year (95% CI 4–66); P = 0.021], but not in other regions. The meta-analysis was limited by the fact that most studies included urban populations, and that the available data were not collected systematically, with standardized methods or definitions, or with representative sampling.
In summary, cumulated data suggest a rise in TDR in east and southern Africa after the ART scale-up. The rise is mostly driven by NNRTI resistance, which is of particular concern, as this drug class constitutes the foundation of current first-line ART regimens and prophylaxis for prevention of mother–child transmission (PMTCT) [3,17].
Because of clinical benefits, international guidelines recommend earlier initiation of ART at CD4 cell counts less than 350 or even less than 500 cells/μl [3,18,19]. Early treatment has attracted significant attention as a promising tool to reduce the number of people acquiring HIV infection . Little is known on what will be the population effects of widespread implementation of early treatment in Africa, in terms of survival, HIV prevention and drug resistance development. A mathematical model on the basis of combined data on transmitted and acquired drug resistance from Kampala, Uganda, and Mombasa, Kenya, predicted that earlier initiation of ART, that is at CD4 cell count less than 350 or less than 500 cells/μl, will lead to increased prevalence of TDR in the coming 10 years, up to 11.6–13.4% and 17.8–18.7%, respectively (B.E. Nichols, K.C. Sigaloff, C. Kityo, K. Mandaliya, in preparation; this is a mathematical model based on data on transmitted and acquired drug resistance from Kampala, Uganda, and Mombasa, Kenya. Earlier initiation of ART is predicted to lead to increased prevalence of TDR, but this risk is outweighed by a reduction in the absolute number of new HIV infections). However, this risk of increased TDR would be outweighed by the reduction in the number of new HIV infections. Moreover, future levels of NNRTI resistance would be diminished because of improved switching practices to second-line bPI regimens.
EFFECT OF PRETHERAPY DRUG RESISTANCE ON THE RESPONSE TO FIRST-LINE ANTIRETROVIRAL THERAPY
The PASER-M cohort study demonstrated that the presence of pretherapy resistance to components of standard first-line treatment more than doubled the risk of virological failure and the further acquisition of DRMs after the first year of first-line ART [21▪]. These findings are in agreement with results from a collaborative analysis in Europe . Pretherapy NNRTI mutations, either as major [21▪,23] or minority variants [24▪], have been associated with an increased risk of virological failure with first-line ART. In addition, previous use of ART or PMTCT has been shown to increase the risk of virological failure and the acquisition of drug-resistant virus during first-line ART [21▪]. These findings support the consideration of bPI-based first-line regimens in individuals who report previous antiretroviral exposure as well as in populations in which TDR levels exceed a yet to be defined threshold.
Pretherapy drug resistance in children is primarily associated with perinatal nevirapine exposure and may be present in up to 60% of infants below 6 months of age when PMTCT fails . Infant prophylaxis with two-drug or three-drug ART regimens can reduce the rate of HIV drug resistance in HIV-infected children to less than 12% . New evidence indicates the superiority of ritonavir-boosted lopinavir-based regimens over nevirapine-based regimens in terms of both efficacy and safety in all infants below the age of 3 years, regardless of whether they were previously exposed to nevirapine [27▪,28]. This poses a dilemma to policymakers because the use of ritonavir-boosted lopinavir implicates higher cost, poor palatability, inconvenient formulation and cold chain requirements.
ACQUIRED DRUG RESISTANCE FOLLOWING FIRST-LINE ANTIRETROVIRAL THERAPY
The WHO-defined early warning indicators (EWI) for HIV drug resistance aim to identify specific programmatic deficiencies that are associated with resistance development during ART . Bennett et al. [30▪▪] assessed data from 907 ART programmes in the region between 2004 and 2009, documenting drug stock-outs in about 40% of sites, more than 20% of loss to follow-up in 40% of sites and ART prescription congruent with national guidelines to 100% of patients in 74% of sites. Important gaps in service delivery and programme performance affect a considerable proportion of ART programmes, particularly with respect to the fragility of procurement and supply systems and inadequate patient retention.
WHO surveys of acquired resistance indicate that after 12 months on ART, 91% of patients achieved full viral load suppression [9▪▪,31]. Among those failing therapy, 72% had drug resistance, implying that 28% of patients potentially switch to costlier second-line regimens unnecessarily. The predicted level of viral susceptibility observed among patients with drug resistance at 12 months suggests that the NRTI component of currently recommended second-line regimens, in combination with a bPI, is likely to be effective for the majority [9▪▪].
Recent observational studies from the region corroborate the notion that routine viral load monitoring prevents accumulation of DRMs and preserves HIV susceptibility. In patients who experienced prolonged first-line failure in the absence of viral load monitoring, 88% had at least one DRM, including high frequencies of accumulated NRTI and NNRTI mutations, for example TAMs, K65R and Q151M, all conferring broad cross-resistance [4▪]. In patients who experienced virological failure after the first year of ART, 70% had at least one DRM [32▪]. Frequent (3-monthly) viral load monitoring in a South African cohort resulted in even less extensive DRM patterns [33▪] (Fig. 1a and b).
There is limited knowledge of DRMs in the African non-B HIV-1 subtypes and their clinical relevance . Studies [35,36] have suggested increased rates of the K65R mutational pattern in subtype C, compared with subtype B, which may be due to the nature of the subtype C RNA template of the viral reverse transcriptase. In a multicountry study [32▪] of mostly subtype A, C or D infections, K65R was frequently selected after failure on stavudine (15%) or tenofovir (28%) containing first-line regimens. After stavudine failure, zidovudine, rather than tenofovir (as recommended by the current WHO guidelines ), might be the preferred second-line NRTI in non-B infected populations in whom stringent viral load monitoring is lacking. Reports of K65R transmission are rare [16▪▪].
Several recent studies [4▪,32▪,37,38] have reported high frequencies of Y181C and G190A mutations, which means that the second-generation NNRTIs etravirine or rilpivirine are unlikely to be effective as part of second-line ART if combined with two NRTIs. Particularly, patients treated with nevirapine seem more likely to have resistance associated with the second-generation NNRTIs than those treated with efavirenz.
The patterns of reverse transcriptase mutations and rates of drug resistance at the time of virological failure seem to be similar for children and adults. However, the rates of virological failure are higher in children, resulting in an overall higher emergence of drug resistance among children . A systematic review on HIV-1 drug resistance after failure of first-line regimens in children in resource-limited settings reported high prevalence of DRMs, 80% for NRTIs, 88% for NNRTIs and 54% for bPIs . Although protease inhibitors are more commonly prescribed in paediatric first-line ART, resistance to this drug class is rare among children  except when ritonavir is used as single protease inhibitor [42,43]. Misclassification of treatment failure in children in the absence of virological monitoring is common [44,45,46▪]. A modelling study  informed by a Thai cohort estimated that even infrequent viral load monitoring is likely to substantially reduce the duration of virological failure.
ACQUIRED DRUG RESISTANCE FOLLOWING SECOND-LINE ANTIRETROVIRAL THERAPY
Two observational studies [48,49▪] have suggested that empiric bPI-based regimens can successfully resuppress HIV-1 replication (in 85–86% of patients), despite the presence of extensive NRTI resistance. By contrast, the ACTG5230 trial, evaluating bPI monotherapy after first-line failure, found that about one-third of patients who achieved less than 400 HIV-RNA copies/ml after 24 weeks appeared to have incomplete suppression at between 40 and 200 HIV-RNA copies/ml [50▪]. In addition, the randomized HIV Star Study [51▪] in Thailand found that second-line bPI monotherapy was virologically inferior to triple therapy in patients failing NNRTI-based first-line therapy (61 versus 83% HIV-RNA<50 copies/ml). Thus, bPI monotherapy should not currently be recommended, and large international trials are underway to further assess this issue. A recent systematic review of patient outcomes on second-line ART in resource-limited settings showed that rates of virological failure are high (23, 27 and 38% at 12, 24 and 36 months, respectively) and associated with poor adherence, rather than resistance development to bPIs, which is likely attributable to their high genetic barrier [52▪]. Therefore, a major concern in Africa is maintaining long-term adherence, especially given that therapeutic options beyond second-line are very expensive and largely nonexistent.
Although data on second-line ART outcomes in children are scarce, most studies [40,41,44,46▪] of children failing first-line ART predict preserved HIV susceptibility to bPIs. A South African study  evaluating 82 children after the use of ritonavir as a single protease inhibitor demonstrated compromised effectiveness of lopinavir/ritonavir-based second-line therapy due to the accumulation of major protease inhibitor mutations, mostly I54 V and V82A/M/S. Among 40 children from Cameroon failing NNRTI-based regimens, response to second-line bPI-based therapy was favourable, with 70% achieving undetectable viral load after 48 weeks .
ACQUIRED DRUG RESISTANCE FOLLOWING PRE-EXPOSURE PROPHYLAXIS
The use of antiretroviral agents by HIV-uninfected persons before sexual exposure to HIV-infected partners, known as preexposure prophylaxis (PrEP), has been evaluated in various trials, with disparate results [55▪,56▪,57▪▪,58,59]. Most recently, the Botswana TDF/FTC Oral HIV Prophylaxis Trial (TDF2) [55▪] and Partners PrEP [56▪] study found that PrEP reduced the risk of HIV acquisition by 62–75%. By contrast, the FEM-PrEP study among HIV-negative women in Kenya, South Africa, and Tanzania was discontinued early because of a lack of protection, due to poor drug adherence [57▪▪]. HIV-1 infection acquired during PrEP has the potential to develop resistance to the agents used [55▪,56▪,58]. Mathematical modelling has suggested that, although TDR may increase, the potential benefits of PrEP outweigh the risks associated with resistance [60–62] and that drug resistance resulting from ART is expected to far exceed that from PrEP . Further studies are needed to determine how best to optimize adherence before widely implementing PrEP in African populations [57▪▪].
ACQUIRED DRUG RESISTANCE IN WOMEN FOLLOWING PREVENTION OF MOTHER-TO-CHILD TRANSMISSION
Given that single-dose nevirapine (sdNVP) for PMTCT has been shown to diminish the effectiveness of subsequent NNRTI-based ART  because of frequent resistance selection , the use of combined antiretroviral regimens is being advocated . In women in Mozambique, sdNVP along with zidovudine reduced postpartum nevirapine resistance . In the Kesho Bora randomized study, HIV-1 drug resistance was present in 17.1% of mothers who received sdNVP along with zidovudine versus 1.4% who received triple ART [67,68]. A study  in Botswana found no DRMs 1 month after discontinuing triple ART for PMTCT. A new WHO strategy (Option B+) proposes to continue triple ART for all women for life . However, no studies have yet investigated the effects on resistance development.
The benefits of routine monitoring of viral load in preventing unnecessary switches and accumulation of drug resistance are increasingly being acknowledged [4▪,71]. A cost–effectiveness analysis estimated that ‘VL-only’ (without additive CD4 cell counts) holds promise as a diagnostic strategy to save costs for long-term ART management by avoiding the incremental costs associated with unnecessary switching [72▪]. A mathematical model of HIV transmission predicted that some form of routine viral load monitoring in patients on ART can reduce TDR [73▪▪].
Very few molecular diagnostic laboratories in the region have the capacity to conduct HIV genotypic resistance testing, of which only six have been WHO-accredited . Because of technical and resource constraints, the use of drug resistance testing in the region is expected to remain restricted to research and population-based surveillance. Of note, a Markov model from South Africa's public sector programme estimated that adding drug resistance testing for patients with virological failure (and retaining patients without resistance on first-line therapy, rather than switching all failures to second-line) is potentially cost neutral and can conserve treatment options .
A comprehensive evaluation of dried blood spots (DBS) for genotyping assay validation and proficiency testing in the WHO laboratory network found that an amplification sensitivity of 1000 HIV-RNA copies/ml can be achieved, that reproducibility and accuracy of nucleotide sequence determination and DRM identification is similar from DBS to that previously determined for plasma and that international shipping at an ambient temperature had no significant effect on amplification success . However, extreme storage conditions may negatively impact on HIV-1 amplification from DBS [77,78]. Current evidence suggests that DBS-based genotyping is probably reliable for population-based applications, but that further optimization of assay conditions and sensitivity is still warranted for individual patient management.
Cumulated data suggest a rising TDR prevalence in east and southern Africa in the context of growing coverage and use of antiretrovirals. The rise in NNRTI resistance is of particular concern, as this drug class is the cornerstone of first-line ART and PMTCT regimens. Important gaps in service delivery and programme performance affect a considerable proportion of ART programmes, particularly with respect to the fragility of procurement and supply systems and inadequate patient retention. To address this issue, national HIV treatment programmes should focus on optimizing their functioning and sustainability, including robust supply chains, access to routine viral load monitoring and alternative regimens, strategies to maximize patient retention and enhanced surveillance of drug resistance. Earlier ART initiation, including TasP, is anticipated to lead to a further rise in TDR in the coming 10 years. However, this risk is likely to be outweighed by a reduction in the number of new HIV infections. Future levels of NNRTI-associated TDR can be diminished by improving strategies for early failure detection and switching practices. Mathematic modelling and economic assessments remain needed to establish the cost–effectiveness of different drug regimens and diagnostic monitoring strategies. Concerted action by international agencies, national governments and ART programmes will be critical to preserve the long-term effectiveness of available ART regimens in Africa.
R.L.H., K.C.E.S. and T.F.R.W. are supported by a grant from Netherlands Ministry of Foreign Affairs (12454) and from NWO/WOTRO-NACCAP (W.07.05.204.00). C.K. is supported by an EDCTP Senior Fellowship (TA 08 40200 022). The authors acknowledge the support of Amsterdam Institute for Global Health and Development, Academic Medical Center of the University of Amsterdam, PharmAccess Foundation and Joint Clinical Research Centre.
The funders had no role in the study design, data collection, data analysis, data interpretation, decision to publish or writing of the report. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.
R.L.H. and K.C.E.S. performed the literature search and drafted the report. All authors contributed to intellectual content, helped to revise the report and approved the final version.
Conflicts of interest
The authors are members of the Affordable Resistance Test for Africa (ART-A) Consortium, a public–private partnership that develops a simplified, affordable HIV drug resistance testing protocol for Africa (http://www.arta-africa.org).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 76–77).
4▪. Sigaloff KC, Hamers RL, Wallis CL, et al. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J Acquir Immune Defic Syndr 2011; 58:23–31.
This international observational study found that the poor specificity of clinico-immunological criteria to detect ART failure may lead to up to half of regimen switches being unnecessary, which exhausts drug options and augments costs. In addition, because of the poor sensitivity of clinico-immunological criteria, prolonged treatment failure leads to accumulation of NRTI and NNRTI resistance mutations.
5. Pasquet A, Messou E, Gabillard D, et al. Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Côte d’Ivoire. PloS One 2010; 5:e13414.
6. Boulle A, Van Cutsem G, Cohen K, et al. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. J Am Med Assoc 2008; 300:530–539.
7▪. Wainberg MA, Zaharatos GJ, Brenner BG. Development of antiretroviral drug resistance. The N Engl J Med 2011; 365:637–646.
This review provides excellent background reading on the genetic differences between HIV-1 subtypes in relation to drug resistance pathways, propensity to acquire certain resistance mutations, HIV-1 susceptibility and how these differences may affect drug cross-resistance and the potential use of specific regimens in resource-limited countries.
8. Wood E, Montaner JS. Time to get serious about HIV antiretroviral resistance. Lancet Infect Dis 2011; 11:723–724.
This is the first WHO report dedicated to HIV drug resistance. This comprehensive review of data generated in WHO surveys in low-income and middle-income countries between 2003 and 2010 reflects the progress in the WHO global strategy for prevention and assessment of HIV drug resistance to date.
10. Somda A, Sangare L, Soro M, et al. Surveillance of transmitted drug-resistant HIV among young pregnant women in Ouagadougou, Burkina Faso. Clin Infect Dis 2012; 54 (Suppl 4):S317–S319.
11. Hunt GM, Ledwaba J, Basson AE, et al. Surveillance of transmitted HIV-1 drug resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005–2009. Clin Infect Dis 2012; 54 (Suppl 4):S334–S338.
12. Ndembi N, Hamers RL, Sigaloff KC, et al. Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala. AIDS 2011; 25:905–910.
13. Sigaloff KC, Mandaliya K, Hamers RL, et al
. High prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS Res Hum Retroviruses 2012; 28:833–837.
14▪▪. Hamers RL, Wallis CL, Kityo C, et al. HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. Lancet Infect Dis 2011; 11:750–759.
This is the largest observational study from Africa to date on HIV drug resistance in antiretroviral-naive persons, including 2436 persons from 11 geographic regions in six countries. This is the first study in Africa to clearly show an association between the time since start of ART roll-out in a region and drug resistance in untreated patients.
15▪. Aghokeng AF, Kouanfack C, Laurent C, et al. Scale-up of antiretroviral treatment in Cameroon is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients. AIDS 2011; 25:2183–2188.
This study, conducted between 1996 and 2007 in Yaoundé, Cameroon, is among the first to report an increasing prevalence of DRMs in antiretroviral-naive persons over time after the roll-out of antiretroviral drugs in Africa.
16▪▪. Gupta RK, Jordan MR, Sultan BJ, et al.
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. Lancet 2012; 380:1250–1258.
This is the most comprehensive assessment to date of available data on HIV-1 drug resistance in untreated patients worldwide, including 26 102 patients in 42 countries. The report suggests a rise in resistance in east and southern Africa, with estimates providing region-specific quantifications of the increase.
20. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493–505.
21▪. Hamers RL, Schuurman R, Sigaloff KC. Effect of pretreatment HIV-1 drug-resistance on immunological, virological and drug-resistance outcomes of first-line antiretroviral treatment: multicentre cohort in six African countries. Lancet Infect Dis 2012; 12:307–317.
This prospective study in six African countries found that the presence of pretherapy resistance to components of standard first-line treatment more than doubles the risk of virological failure and the further acquisition of DRMs after the first year of first-line ART.
22. Wittkop L, Gunthard HF, de Wolf F, et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Lancet Infect Dis 2011; 11:363–371.
23. Li JZ, Paredes R, Ribaudo HJ, et al. Relationship between minority nonnucleoside reverse transcriptase inhibitor resistance mutations, adherence, and the risk of virologic failure. AIDS 2012; 26:185–192.
24▪. Li JZ, Paredes R, Ribaudo HJ, et al. Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis. J Am Med Assoc 2011; 305:1327–1335.
This pooled analysis shows that low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, are significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.
25. Hunt GM, Coovadia A, Abrams EJ, et al. HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS 2011; 25:1461–1469.
26. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med 2012; 366:2368–2379.
27▪. Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 2012; 366:2380–2389.
This trial indicates the superiority of ritonavir-boosted lopinavir-based regimens over nevirapine-based regimens in terms of both efficacy and safety in all infants below the age of 3 years, regardless of whether they were previously exposed to nevirapine.
28. Penazzato M, Prendergast A, Tierney J, et al. Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age. Cochrane Database Syst Rev 2012; 7:CD004772.
29. Bennett DE, Bertagnolio S, Sutherland D, Gilks CF. The World Health Organization's global strategy for prevention and assessment of HIV drug resistance. Antivir Ther 2008; 13 (Suppl 2):1–13.
30▪▪. Bennett DE, Jordan MR, Bertagnolio S, et al. 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. Clin Infect Dis 2012; 54 (Suppl 4):S280–S289.
This aggregated report of WHO-defined EWIs for HIV drug resistance includes data from 907 ART programmes in Africa. Important gaps in service delivery and programme performance affect a considerable proportion of ART programmes, particularly with respect to the fragility of procurement and supply systems and inadequate patient retention.
31. Jordan MR, Bennett DE, Bertagnolio S, et al. World Health Organization surveys to monitor HIV drug resistance prevention and associated factors in sentinel antiretroviral treatment sites. Antivir Ther 2008; 13 (Suppl 2):15–23.
32▪. Hamers RL, Sigaloff KC, Wensing AM, et al.
Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies. Clin Infect Dis 2012; 54:1660–1669.
This prospective study in six African countries describes patterns of resistance mutations according to first-line regimens received. The study suggests that early failure detection limits the accumulation of resistance. Because of the high frequency of K65R after stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART.
33▪. Wallis CL, Papathanasopoulos M, Fox MP, et al. Low rates of nucleoside reverse transcriptase inhibitor (NRTI) resistance detected in a well monitored cohort in South Africa accessing antiretroviral therapy. Antivir Ther 2012; 17:313–320.
This study in a closely monitored cohort in South Africa suggests that frequent (3-monthly) viral load monitoring limits the level and complexity of resistance observed, preserving susceptibility to second-line options.
34. Hemelaar J, Gouws E, Ghys PD, Osmanov S. Global trends in molecular epidemiology of HIV-1 during 2000-2007. AIDS 2011; 25:679–689.
35. Coutsinos D, Invernizzi CF, Xu H, et al. Factors affecting template usage in the development of K65R resistance in subtype C variants of HIV type-1. Antivir Chem Chemother 2010; 20:117–131.
36. Coutsinos D, Invernizzi CF, Xu H, et al. Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1. J Virol 2009; 83:2029–2033.
37. Wallis CL, Mellors JW, Venter WD, et al. Varied patterns of HIV-1 drug resistance on failing first-line antiretroviral therapy in South Africa. J Acquir Immune Defic Syndr 2010; 53:480–484.
38. van Zyl GU, van der Merwe L, Claassen M, et al. Antiretroviral resistance patterns and factors associated with resistance in adult patients failing NNRTI-based regimens in the Western Cape, South Africa. J Med Virol 2011; 83:1764–1769.
39. Sutcliffe CG, van Dijk JH, Bolton C, et al. Effectiveness of antiretroviral therapy among HIV-infected children in sub-Saharan Africa. Lancet Infect Dis 2008; 8:477–489.
40. Sigaloff KC, Calis JC, Geelen SP, et al. HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: a systematic review. Lancet Infect Dis 2011; 11:769–779.
41. Frange P, Briand N, Avettand-fenoel V, et al. Lopinavir/ritonavir-based antiretroviral therapy in human immunodeficiency virus type 1-infected naive children: rare protease inhibitor resistance mutations but high lamivudine/emtricitabine resistance at the time of virologic failure. Pediatric Infect Dis J 2011; 30:684–688.
42. van Zyl GU, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatric Infect Dis J 2009; 28:1125–1127.
43. Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses 2011; 27:945–956.
44. Barth RE, Tempelman HA, Smelt E, et al. Long-term outcome of children receiving antiretroviral treatment in rural South Africa: substantial virologic failure on first-line treatment. Pediatric Infect Dis J 2011; 30:52–56.
45. Barth RE, Aitken SC, Tempelman H, et al. Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype-C-infected patients. Antivir Ther 2012; 17:377–386.
46▪. Westley BP, Delong AK, Tray CS, et al. Prediction of treatment failure using 2010 World Health Organization guidelines is associated with high misclassification rates and drug resistance among HIV-infected Cambodian children. Clin Infect Dis 2012; 55:432–440.
This paediatric cohort study in Cambodia found that lack of virological monitoring results in unacceptable treatment failure misclassification, leading to premature ART switch and resistance accumulation.
47. Schneider K, Puthanakit T, Kerr S, et al. Economic evaluation of monitoring virologic responses to antiretroviral therapy in HIV-infected children in resource-limited settings. AIDS 2011; 25:1143–1151.
48. Hosseinipour MC, Kumwenda JJ, Weigel R, et al. Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline. HIV Med 2010; 11:510–518.
49▪. Sigaloff KC, Hamers RL, Wallis CL. Second-line antiretroviral treatment successfully re-suppresses drug-resistant HIV-1 after first-line failure: prospective cohort in sub-Saharan Africa. J Infect Dis 2012; 205:1739–1744.
This study in six African countries also suggests that bPI-based regimens can successfully resuppress HIV-1 replication despite the presence of extensive NRTI resistance.
50▪. Bartlett JA, Ribaudo HJ, Wallis CL, et al.
Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS 2012; 26:1345–1354.
This randomized study, evaluating bPI monotherapy after first-line failure in low-resource settings, found that about one-third of patients who achieved less than 400 HIV-RNA copies/ml after 24 weeks appeared to have incomplete suppression at between 40 and 200 copies/ml.
51▪. Bunupuradah T, Chetchotisakd P, Ananworanich J, et al.
A randomized comparison of second-line lopinavir/ritonavir monotherapy vs. tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI-regimens: the HIV STAR study. Antivir Ther 2012 [Epub ahead of print]. doi:10.3851/IMP2222.
This randomized study found that second-line bPI monotherapy was virologically inferior to triple therapy in patients failing NNRTI-based first-line.
52▪. Ajose O, Mookerjee S, Mills EJ, et al. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. AIDS 2012; 26:929–938.
This meta-analysis found poor second-line treatment outcomes in resource-limited settings. Failure of second-line treatment seems to be due to suboptimal adherence rather than development of resistance to protease inhibitors, which have a high genetic barrier to resistance.
53. Zyl GU, Rabie H, Nuttall JJ, Cotton MF. It is time to consider third-line options in antiretroviral-experienced paediatric patients? J Int AIDS Soc 2011; 14:55.
54. Fokam J, Salpini R, Santoro MM, et al. Drug resistance among drug-naive and first-line antiretroviral treatment-failing children in Cameroon. Pediatric Infect Dis J 2011; 30:1062–1068.
55▪. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367:423–434.
This randomized controlled trial (RCT) in Botswana found that daily oral tenofovir–emtricitabine prophylaxis prevents HIV infection in sexually active heterosexual adults. One participant, who was randomized to receive daily oral tenofovir–emtricitabine, acquired resistance to both antiretrovirals (K65R, M184V and A62V mutations).
56▪. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367:399–410.
This RCT among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda found that either oral tenofovir or tenofovir–emtricitabine protects against HIV infection. Two out of eight who acquired HIV, despite prophylaxis, developed antiretroviral resistance.
57▪▪. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367:411–422.
This RCT among HIV-negative women in Kenya, South Africa and Tanzania, which was stopped early because of lack of efficacy, found that oral tenofovir–emtricitabine prophylaxis did not significantly reduce the rate of HIV infection. Drug adherence appeared to be low (<40%).
58. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:2587–2599.
59. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329:1168–1174.
60. Supervie V, Barrett M, Kahn JS, et al. Modeling dynamic interactions between preexposure prophylaxis interventions & treatment programs: predicting HIV transmission & resistance. Sci Rep 2011; 1:185.
61. Dolling D, Phillips AN, Delpech V, et al. Evaluating the extent of potential resistance to preexposure prophylaxis within the UK HIV-1-infectious population of men who have sex with men. HIV Med 2012; 13:309–314.
62. Abbas UL, Hood G, Wetzel AW, Mellors JW. Factors influencing the emergence and spread of HIV drug resistance arising from rollout of antiretroviral preexposure prophylaxis (PrEP). PloS One 2011; 6:e18165.
63. Parikh UM, Mellors JW. HIV-1 drug resistance resulting from antiretroviral therapy far exceeds that from preexposure prophylaxis. Clin Infect Dis 2012; 55:303–304.
64. Jourdain G, Ngo-Giang-Huong N, Le CS, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004; 351:229–240.
65. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 2001; 15:1951–1957.
66. Micek MA, Blanco AJ, Carlsson J, et al. Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine. J Infect Dis 2012; 205:1811–1815.
67. de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis 2011; 11:171–180.
68. Group TKBS. Maternal HIV-1 disease progression 18-24 months postdelivery according to antiretroviral prophylaxis regimen (triple-antiretroviral prophylaxis during pregnancy and breastfeeding vs zidovudine/single-dose nevirapine prophylaxis): the Kesho Bora randomized controlled trial. Clin Infect Dis 2012; 55:449–460.
69. Souda S, Gaseitsiwe S, Georgette N, et al.
No clinically significant drug resistance mutations in HIV-1 subtype c-infected women after discontinuation of protease inhibitor-based or NRTI-based HAART for PMTCT. 19th Conference on Retroviruses and Opportunistic Infections; Seattle, Washington, USA; 5–8 March 2012 [Abstract #1018].
71. Hosseinipour MC, van Oosterhout JJ, Weigel R, et al. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS 2009; 23:1127–1134.
72▪. Hamers RL, Sawyer AW, Tuohy M, et al.
Cost-effectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis. AIDS 2012; 26:1663–1672.
This modelling exercise offers an alternative perspective by assessing the cost-effectiveness of viral load as an alternative to CD4 cell count monitoring following ART initiation. The study found that viral load monitoring could save costs by identifying the right people to switch onto more expensive second-line regimens, and by switching patients to second-line treatment more quickly before they are at a higher risk of clinical disease progression and death.
73▪▪. Phillips AN, Pillay D, Garnett G, et al. Effect on transmission of HIV-1 resistance of timing of implementation of viral load monitoring to determine switches from first to second-line antiretroviral regimens in resource-limited settings. AIDS 2011; 25:843–850.
This model estimates that the introduction of routine viral load monitoring to guide regimen switches will substantially reduce the prevalence of TDR. There is an eventual need for some form of cheap and practical viral load monitoring in resource-limited settings to preserve current first-line drugs for the long term.
74. Parkin N, Bremer J, Bertagnolio S. Genotyping external quality assurance in the World Health Organization HIV drug resistance laboratory network during 2007-2010. Clin Infect Dis 2012; 54 (Suppl 4):S266–S272.
75. Rosen S, Long L, Sanne I, et al. The net cost of incorporating resistance testing into HIV/AIDS treatment in South Africa: a Markov model with primary data. J Int AIDS Soc 2011; 14:24.
76. Parkin N, de Mendoza C, Schuurman R, et al. Evaluation of in-house genotyping assay performance using dried blood spot specimens in the Global World Health Organization laboratory network. Clin Infect Dis 2012; 54 (Suppl 4):S273–S279.
77. Aitken SC, Wallis CL, Stevens W, et al
. Effect of storage conditions on the detection of HIV-1 minority viral populations in DBS using population-based genotyping [Abstract #741]. 19th Conference on Retroviruses and Opportunistic Infections; Seattle, Washington, USA; 5–8 March 2012. [Abstract #741].
78. Ziemniak C, Mengistu Y, Ruff A, et al. Use of dried-blood-spot samples and in-house assays to identify antiretroviral drug resistance in HIV-infected children in resource-constrained settings. J Clin Microbiol 2011; 49:4077–4082.