HIV treatment breaks lead to drug resistance in the female genital tract

Antiretroviral treatment interruptions of 48 hours or more are associated with the emergence of resistant strains of HIV in the female genital tract, investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The study included 102 women in Kenya who started first-line antiretroviral therapy based on a non-nucleoside reverse transcriptase inhibitor (NNRTI). Drug-resistant virus was detected in the genital tract of five women in the twelve months after treatment was started. Treatment interruptions were the most important risk factor for this outcome.

“We found that ART [antiretroviral therapy] adherence was a key determinant of genital tract resistance and that treatment interruptions of whatever cause lead to a substantial increase in the hazard of detecting genotypic resistance to antiretrovirals in female genital tract secretions,” write the authors. “Efforts to prevent treatment interruptions by improving program effectiveness, promoting adherence and timely refills, and avoiding the use of more toxic antiretroviral agents could therefore play an important role in reducing transmitted drug resistance.”

First-line HIV therapy often comprises two nucleoside reverse transcriptase inhibitors (NRTIs) combined with an NNRTI. This treatment can have a powerful and durable anti-HIV effect. However, it requires high levels of adherence. Drug-resistant strains of HIV can emerge with poorer adherence. Older drugs in the NNRTI class, nevirapine (Viramune) and efavirenz (Sustiva or Stocrin), have a low barrier to resistance.

Little is currently known about the emergence of drug-resistant virus in the genital tract of women treated with NNRTI-based therapy. This is an important gap in knowledge as drug-resistant virus is potentially transmissible.

Investigators therefore designed a prospective study involving women who started first-line HIV treatment in Mombasa between 2005 and 2008. During the first twelve months after starting therapy viral load was monitored at three-monthly intervals in both plasma and the genital tract. Samples with viral load above 1000 copies/ml were sent for resistance testing. The investigators conducted analysis to see which factors were associated with the emergence of drug-resistant virus in the genital tract.

Overall, the women had high levels of adherence to their antiretroviral therapy. Assessed by pill count, median adherence was 97%. However, there were 40 treatment interruptions. Their median duration was four days. Median pill-count adherence following treatment interruptions was just 83%.

Drug-resistant virus was detected in the blood of nine women (incidence, 10 per 100 person-years) and in the genital secretions of five individuals (incidence, 5.5 per 100 person-years). All five women with resistant HIV in their genital secretions also had resistant virus in their blood.

The investigators’ first set of analysis showed that a number of factors were associated with genital tract resistance. These included treatment interruptions (p = 0.006), pill-count adherence (p = 0.001) and a higher baseline viral load (p = 0.04).

But only treatment interruptions remained significant after controlling for potentially confounding factors. Interruptions were associated with a more than 14-fold increase in the risk of genital tract resistance (aHR = 14.2; 95% CI, 1.3-158.4; p = 0.03).

“The reasons for treatment interruption in this study included both unavoidable discontinuations due to drug toxicity or systemic illness and avoidable interruptions due to late refills, when it is likely that consecutive doses were missed,” note the investigators. “Despite a comprehensive program of adherence support including pre-ART counseling, directly administered therapy during the first month of treatment, a support group, pill boxes and transportation reimbursements, we were unable to prevent these events.”

Transport problems and pharmacy stock-outs have emerged as major barriers to adherence in resource-limited settings. The investigators are concerned that “such barriers may lead to the development of genital tract resistance due to treatment interruptions, suggesting an increased risk for transmission of drug-resistant virus”.

Graham SM et al. Antiretroviral treatment interruptions predict female genital shedding of genotypically resistant HIV-1 RNA. J Acquir Immune Defic Syndr, online edition. DOI: 10.1097/QAI.0b013e31825bd703, 2012.