CROI: Recent OIs or AIDS strongest predictors of development of resistance in South African first-line failures

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A recent opportunistic infection on treatment or World Health Organization (WHO) stage 4 HIV disease prior to starting treatment were the strongest predictors of the development of resistance after the failure of first-line treatment in a large South African cohort, the Fourteenth Conference on Retroviruses and Opportunistic Infections heard this week.

Investigators from South Africa and the United States reported on the early experiences of two HIV clinics in KwaZulu Natal province following the roll out of triple-drug antiretroviral therapy (ART) in South Africa.

The investigators were aware that almost 20% of the 3,000 ART-treated patients at these clinics had previously received single- and/or dual-nucleoside ART prior to receiving ‘first-line’ therapy consisting of either efavirenz- or nevirapine-based ART in combination with zidovudine and lamivudine (AZT/3TC). A further 9% had been exposed to single dose nevirapine for prevention of mother-to-child transmission.

Glossary

WHO stage

A simplified system to describe four clinical stages of HIV-related disease, based on clinical parameters (symptoms, weight loss and different opportunistic infections) rather than decreasing CD4 cell count. Stage I is asymptomatic, stage II mild symptoms, stage III advanced symptoms and stage IV severe symptoms (an AIDS diagnosis).

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

first-line therapy

The regimen used when starting treatment for the first time.

opportunistic infection (OI)

An infection that occurs more frequently or is more severe in people with weakened immune systems, such as people with low CD4 counts, than in people with healthy immune systems. Opportunistic infections common in people with advanced HIV disease include Pneumocystis jiroveci pneumonia; Kaposi sarcoma; cryptosporidiosis; histoplasmosis; other parasitic, viral, and fungal infections; and some types of cancer. 

inter-quartile range

The spread of values, from the smallest to the largest. The inter-quartile range (IQR) only includes the middle 50% of values and measures the degree of spread of the most common values.

This observational cohort study included 119 (4% of the cohort) who had experienced virological failure – defined as a plasma viral load above 1,000 copies/mL – since beginning triple-drug ART in January 2005. Just over one in five (21.3%) experienced AIDS-defining illnesses (WHO stage IV disease); and almost half (45.4%) were still receiving their ART regimen at the time of virological failure.

The standard first-line regimen was NNRTI-based: 43.3% took d4T/3TC/efavirenz and 40% took d4T/3TC/nevirapine.

The median viral load at virological failure was 4.27 log10 copies/ml (interquartile range [IQR], 3.66 to 4.90 log10copies/ml) and the median CD4 cell count was 151 cells/mm3 (IQR, 104 to 229/mm3).

The Trugene genotypic assay was used to identify drug resistance mutations. Just under three-quarters (71%) of the individuals with virological failure had at least one significant resistance mutation identified; more than half (60%) had mutations associated with resistance to two drug classes; and triple-class resistance was seen in 1.7%.

The most frequently seen mutation (54.6% of the cohort) was M184V, which confers resistance to lamivudine. Almost three-quarters of the cohort (72%) had at least one NNRTI-associated mutation (K103N occurring in 43%). A further 3.4% were found to have significant protease inhibitor-associated mutations, and 17.2% had thymidine analogue mutations associated with exposure to d4T or AZT.

Exploratory multiple logistic regression analysis that adjusted for baseline age, gender, CD4 cell count, WHO stage, haemoglobin, and viral load identified recent opportunistic infections (Odds Ratio [OR] 3.1, p = 0.01), WHO stage 4 HIV disease (OR 4.14, p=0.05) and viral load at time of detected failure below 300,000 copies/ml (OR 5.96, p=0.04) as significant risk factors for virological failure with subsequent drug resistance.

Vincent Marconi of Brigham & Women’s Hospital, Boston, presenting the results, said that the fact that viral load above 300,000 copies/ml was not associated with drug resistance was probably explained by the fact that the patients with the highest viral load most likely had the worst adherence, and had simply stopped taking medication altogether.

The investigators based the patients’ second-line ART on the genotype resistance data obtained here, and follow-up continues for a further six months in order to determine whether this resulted in a return to full virological suppression.

References

Marconi VC et al. Prevalence of HIV-1 drug resistance after virologic failure of first HAART regimen in South Africa: initial results of the South Africa Resistance Cohort Study Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 94, 2007.