The female genital tract appears to be a 'reservoir' for ongoing HIV replication, even during effective antiretroviral therapy, an international team of investigators report in Clinical Infectious Diseases. “The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART [combination antiretroviral therapy] and affect the use of cART to prevent sexual and perinatal transmission of HIV-1,” suggest the authors.
However, the accumulating evidence showing that antiretroviral therapy reduces the risk of HIV transmission casts doubt on the real-world significance of the study’s findings.
Modern combination antiretroviral therapy is highly effective at suppressing HIV replication in both blood and the genital tract. However, relatively little is known about the impact of HIV therapy on genital tract viral load according to sex and HIV subtype. These are potentially important questions given evidence suggesting that genital tract viral load in untreated individuals is higher in women than men, especially among those infected with HIV subtype C.
Investigators from the ACTG A5185s trial therefore designed a study involving men and women in seven different countries (Brazil, India, Malawi, Peru, South Africa, United States and Zimbabwe) who started treatment with three different combinations of antiretroviral drugs. Viral load in blood plasma and genital fluids was monitored at baseline and again after 48 and 96 weeks of treatment.
Just over half (55%) of men were infected with HIV subtype B and 45% with subtype C. Three-quarters of women (76%) had subtype C infection and 24% were infected with HIV subtype B.
Median CD4 cell count at baseline was 193 cells/mm3 and did not differ by either sex or subtype. The median blood viral load on entry to the study was approximately 80,000 copies/ml. Once again, there were no significant differences by subtype or sex.
HIV was detected in 82% of semen samples collected at baseline and in 86% of cervical samples.
Women with subtype C infection had the highest genital tract viral load at baseline, a median of approximately 125,000 copies/ml. This compared to a median baseline genital tract viral load of 10,000 copies/ml for women with subtype B infection; 10,000 copies/ml for men with HIV subtype C and 6000 copies/ml for men with subtype B infection.
The difference in genital tract viral load persisted and remained significant after adjustment for viral load in blood plasma, age and the presence of sexually transmitted infections (p = 0.037).
Antiretroviral therapy was highly effective at suppressing viral load in both blood and the genital compartment. At both weeks 48 and 96 HIV was undetectable in the genital secretions of 90% of participants. Similar proportions of participants had undetectable viral load in blood.
However, closer analysis of the results revealed significant differences in genital tract viral load according to gender and HIV subtype.
At week 48, 84% of women and 94% of men had an undetectable genital tract viral load (p = 0.006). This difference persisted at week 96, when the proportion of women with genital tract viral load below the limit of detection remained at 84%, whereas the proportion of men had increased to 97% (p = 0.002). The results were unaffected after adjustment to take into account the use of hormonal contraception.
“Women with either subtype were significantly less likely to have genital tract viral load below the limit of quantification at weeks 48 and 96,” the investigators emphasise. “Differences in genital tract drug penetration between men and women might explain this finding.”
The authors believe these findings are especially noteworthy as the assays used to monitor HIV levels in the female genital tract were significantly less sensitive than those used to assess shedding of HIV in semen (lower limit of detection, 1575 copies/ml vs 120 copies/ml).
“We have demonstrated that genital tract viral load differs according to gender and HIV subtype with higher levels in women with subtype C virus,” conclude the authors. “Moreover, women are less likely to suppress genital tract viral load after initiating cART.” They suggest their findings may have implications for the use of HIV treatment as prevention.
However, the HPTN 052 study showed that antiretroviral therapy that suppressed viral load in the blood reduced the risk of transmission by 96%. The study was conducted in settings where subtype C virus predominate. If low-level genital tract replication is widespread among women taking antiretroviral therapy, it does not appear to have translated into a real risk of transmission in the only large randomised study of the impact of antiretroviral therapy on sexual transmission conducted to date.
Fiscus SA et al. Changes in HIV-1 subtypes B and C in genital tract RNA in women and men after initiation of antiretroviral therapy. Clin Infect Dis, online edition, 2013.