Drug resistance in low- and middle-income countries
Polly Clayden, HIV i-Base
Several studies presented at the 27th International Workshop on HIV Drug Resistance and Treatment Strategies described rates of HIV drug resistance in low- and middle-income countries (LMICs).
High rates of pretreatment drug resistance in women
NNRTI pretreatment drug resistance was nearly twice as high in women compared to men in a pooled analysis, conducted by WHO, in LMICs in Africa, South America and South East Asia. 
These findings were based on analyses of data from 11 nationally representative surveys: Cameroon, Namibia, Uganda, Zimbabwe, Argentina, Brazil, Colombia, Guatemala, Mexico, Nicaragua and Myanmar. The surveys were performed during 2014–2017 and included 4275 people starting first-line ART – as reported in the WHO HIVDR report 2017.
Women comprised 38% of the survey population with higher proportions in sub-Saharan Africa: 56.7–65.4%.
Eight of 11 countries had NNRTI pretreatment drug resistance prevalence estimates exceeding 10% in women compared to 5 of 11 for men: 12.2% (95% CI 9.1 to 16.3) vs 6.3% (95% CI 5.0 to 8.1), p<0.0001, in women and men respectively.
Prevalence of NRTI pretreatment drug resistance was greater than 10% in women in 2/11 countries (Nicaragua and Mexico) and less than 10% in men in all countries. Prevalence of PI pretreatment drug resistance was less than 5% overall in all countries.
The authors concluded that this survey suggests the urgent need for alternative non-NNRTI regimen for women and reinforces the need for routine nationally representative pretreatment drug resistance surveys.
Drug resistance mutations and virologic failure in women on efavirenz-based ART following PROMISE study
Pre-efavirenz-ART drug resistance was detected in approximately 16% of women and viral failure in approximately 18% of women, who participated in PROMISE 1077BF and subsequently started efavirenz-based ART for their own health. 
PROMISE compared a PMTCT strategy (AZT and single-dose nevirapine plus a 1–2 week postpartum tail of tenofovir and emtricitabine) to PI-based ART in women not indicated for treatment for their own health (<350 cells/mm3) at the time the study was conducted. Antenatal ART resulted in significantly lower rates of early HIV transmission than the PMTCT strategy.
The resistance study, conducted in Kenya, was designed to assess whether pre-efavirenz-ART drug resistance in PROMISE participants who subsequently started efavirenz-based ART was associated with viral failure.
Pre-efavirenz-ART drug resistance was found in 209/1316 women: 15.9% (95% CI 13.9 to 18%).
Viral failure was found in 233/1316 women (95% CI 15.7 to 19.9%).
There was no difference in rates of viral failure by 6–12 months in women who were previously randomised to ART or PMTCT strategies.
Pre-efavirenz-ART drug resistance to multiple drug classes (>1 NRTI and >1 NNRTI) was associated with increased viral failure (7/8 women), p<0.0001.
High prevalence of pretreatment drug resistance associated with poor treatment outcomes in South Africa
The ITREMA study, conducted at a rural clinical site in Limpopo, found pretreatment drug resistance prevalence of 13% in this population.  Pretreatment drug resistance was significantly associated with poor treatment outcomes. This association was mainly driven by dual NNRTI and NRTI resistance.
ITREMA is an open-label randomised controlled study in adults either starting first-line or stable on first-line ART. The intervention arm includes intensive viral load monitoring, drug levels and resistance testing. The control arm has viral load monitoring according to South African guidelines.
At time of analysis, 501 participants were recruited. A total of 207 were enrolled while starting first-line ART: 60.4% women; 96.6% received tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV); overall 6.3% (13/207) reported prior ART (46.2% [6/13] TDF/FTC/EFV).
Pretreatment samples were available and sequencing successful for 194/207 and 12.9% (25) had pretreatment drug resistance: 19/25 NNRTI and 6/25 NNRTI + NRTI.
At week 48, dual class pretreatment drug resistance was strongly associated with viral load >1000 copies/mL and treatment failure: aOR 2.56 (95% CI 2.00 to 3.27).
The authors noted recent or current undisclosed ART use in a subset of participants and suggest that efforts to uncover previous exposure are indicated in clinical practice.
High levels of viral load suppression in Malawi but emerging drug resistance among those with virological failure
A prospective study of 921 people starting NNRTI-based regimens between October 2009 and December 2013 at 10 sentinel ART sites in Malawi found approximately 85% of participants in follow up had undetectable viral load at 24 and 36 months. 
But, loss to follow up was very high in this study: 33.7% and 50.6% overall at 24 and 36 months. Smaller proportions of participants transferred out, stopped ART, had regimen substitutions or suspected or confirmed TB. At 36 months, only 340 (36.9%) were documented to be on ART.
There was a very high prevalence of dual NNRTI/NRTI resistance among people with detectable viral load at follow up. M184V accounted for most NRTI resistance; NNRTI resistance was largely due to K103N or Y181C. Almost all participants with drug resistance had adequate nevirapine drug levels.
Drug resistance in adults failing protease inhibitor-based ART in KwaZulu-Natal
A retrospective analysis ART resistance among adults not responding to second-line PI-based ART in Kwazulu-Natal found increasing triple class resistance in this population.
A total of 166 patient records (87 men and 79 women) were assessed. Over half (55.4%) were receiving AZT, 3TC and lopinavir/r. Other regimens included abacavir, tenofovir, emtricitabine and atazanavir/r. The majority of patients received a PI plus two NRTIs; 8 patients received lopinavir/r with three NRTIs.
Of the group, 35.5% had major PI resistance mutations; 30% had three or more major PI mutations; 28.9% had 154V; 25% had V82A; 22.7% had M461; 11.4% had L76V; 6% had 184V; 5.4% had M46L and 2.4% other PI mutations.
Most frequent NRTI mutations were TAMs. Respectively 68% and 65% remained susceptible to AZT and tenofovir. Over 50% had high level resistance to first generation NNRTIs.
The authors noted increasing frequency of PI resistance: 35.5% reported in this study compared with 6.7% reported in 2009–2010. And increasing triple-class resistance in patients with second-line failure.
There were relatively low levels darunavir, etravirine, AZT and tenofovir resistance observed in patients with ART failure which they suggest might warrant use of these antiretrovirals in third-line regimens.
They recommended continued surveillance of drug resistance levels in LMICs to guide management of patients on ART. 
Several other presentations at the workshop told similar stories.
Atypical resistance patterns at time of first-line failure were shown in a study conducted in Uganda and South Africa, suggesting previous undisclosed ART use, increasing transmitted drug resistance or different resistance patterns in non-sub type B viruses to those usually seen in subtype B. 
Another Ugandan study suggested a majority of successful treatment outcomes in about 87% of people after 48 months but high prevalence of drug resistance in those with viral failure. 
But a study from Cameroon showed decreasing rates of drug resistance among patients failing first-line ART from 2016, which the authors suggested could be explained by earlier detection of virological failure following the introduction of Test and Treat and perhaps the availability of newer drugs and regimens. 
All references are to the programme and abstracts of the 27th International Workshop on HIV Drug Resistance and Treatment Strategies. 22–23 October 2018. Johannesburg, South Africa unless otherwise stated.
- Inzaule S et al. Pretreatment HIV drug resistance in women in low- and middle-income countries. Oral abstract 1.
- Boyce CL et al. HIV drug resistance mutations associated with virologic failure in women on efavirenz-based ART following PROMISE study. Poster abstract 13.
- Hermans L et al. Pretreatment drug resistance is associated with virological failure in South African
patients on first-line ART –findings from the ITREMA trial. Oral abstract 2.
- Bello G et al. Population-based monitoring of HIV drug resistance emerging in HIV-positive individuals during antiretroviral treatment and related programme factors in sentinel ART sites in Malawi. Oral abstract 3.
- HIV drug resistance in adults failing protease inhibitor (PI)-based antiretroviral therapy (ART) in KwaZulu-Natal. Oral abstract 6.
- McCluskey S et al. Atypical resistance patterns at the time of failure on first-line antiretroviral therapy in Uganda and South Africa. Oral abstract 4.
- Asio J et al. Predictors of virological failure and HIV drug resistance in a Ugandan population after 48 months on antiretroviral therapy. Oral abstract 5.
- Fokam J et al. Declining trends of HIV-1 drug resistance among patients failing antiretroviral treatment following the Test and Treat implementation in Cameroon. Poster abstract 10.