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

Abstract

SummaryBackgroundThe 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.MethodsWe 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.FindingsStudy-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.InterpretationOur 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.FundingBill & Melinda Gates Foundation and the European Community's Seventh Framework Programme

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

“…Mutation types observed were also consistent with claims that TDR in resource-limited settings is driven mainly by (N)NRTI resistance 29,30 and with the fact that AZT/3TC/NVP or AZT/ 3TC/EFV is the recommended first-line regimen in the Ugandan national guidelines. 31 The lack of time trends in pretherapy resistance prevalence, however, contrasted with reports that TDR is on the rise globally, 3,29,30,32,33 with the most extreme being East Africa experiencing a 29% increase/year, 34 but could be limited by our small number of TDR cases leading to a lack of statistical power, or differences in antiretroviral rollout staging compared to previous reports. These results were also limited by the cohort's heterogeneity in disease progression status, 32 the reversion and/or persistence of selected mutations, [35][36][37][38][39][40][41] as well as the often inaccurate self-reported treatment-naive status as shown by our HPLC-MS/MS analysis and the lack of pregnancyrelated NVP usage information.…”

“…In the UARTO pilot study (Kampala/AMU), a total of 62% participants were female with a median age of 36 years (IQR [30][31][32][33][34][35][36][37][38][39][40], baseline log viral load of 5.5 (IQR 4.9-5.8), and baseline CD4 count of 60 (IQR 12-136). All AMU participants received generic fixed dose combinations of d4T/3TC/ NVP as a first regimen.…”

“…All AMU participants received generic fixed dose combinations of d4T/3TC/ NVP as a first regimen. In the UARTO main cohort (Mbarara/MBA), a total of 70% of participants were female with a median age of 35 years (IQR [29][30][31][32][33][34][35][36][37][38][39], baseline viral load of 5.1 log 10 HIV-RNA copies/ml (IQR 4.7-5.6), and baseline CD4 count of 131 . Initial regimens were primarily NVP based (86%) and EFV based (12%) in combination with lamivudine (3TC) and zidovudine (AZT) backbones.…”

Time to reduce CD4+ monitoring for the management of antiretroviral therapy in HIV-infected individuals

“…Reflecting this growing evidence base, the WHO released a technical document in March 2014 summarising the considerations in support of a move towards stopping routine CD4 + monitoring where VL monitoring is available. [13] In the most recent WHO guidelines, [14] access to VL monitoring is recommended as the preferred approach to support adherence, detect treatment failure early, assess transmission risk and avoid keeping individuals on failing regimens, especially as rates of drug resistance begin to rise in developing countries. Resources and research and development should therefore be channelled to both VL and HIV drug resistance testing.…”

The emergence of drug resistant HIV variants and novel anti–retroviral therapy

“…Many studies have addressed the prevalence of ARDR to date [46][47][48] . In general, it seems that the prevalence of transmitted HIV drug resistance (TDR) has followed a steady pattern in developed countries [49] , recently conducted surveys in western Europe and United States have shown that the trend of TDR has become stable in recent years [50,51] .…”