Drugs from the nucleoside reverse transcriptase inhibitor (NRTI) class of antiretrovirals achieve good concentrations in the female genital tract and may have the potential to reduce the risk of sexual transmission of HIV, US researchers report in the March 1st edition of Clinical Infectious Diseases. Particularly high concentrations of 3TC (lamivudine, Epivir) and tenofovir (Viread) in the genital tract were observed.
But the investigators found that protease inhibitors and non-nucleoside reverse transcriptase inhibitors achieved concentrations in the female genital tract that were between 1% - 33% of those observed in the blood. Nevertheless, viral load remained suppressed in the genital tract of women with good adherence.
This latest research may further fuel the debate about the infectiousness, or otherwise, of patients taking successful anti-HIV therapy. Swiss HIV doctors issued a statement in late January stating that HIV-positive individuals who were adherent to their anti-HIV therapy, achieving an undetectable viral load for at least six months, and who were free of sexually transmitted infections should not be considered infectious.
Anti-HIV treatment reduces the risk of mother-to-child transmission of HIV. There is also evidence from some studies that it reduces the risk of sexual transmission of the virus. This is likely to be because antiretroviral therapy lowers viral load in the genital tract. Research has shown that reductions in viral load during HIV therapy in cervicovaginal fluids parallel those in blood. But, viral load can diverge in these two compartments and the development of drug-resistant HIV in the genital tract, but not blood, has been observed in some patients.
It is currently unclear if differences in viral load in the female genital tract and blood are due to differing concentrations of antiretroviral drugs in the two compartments. Some studies do suggest that concentrations of protease inhibitors and NNRTIs are lower in the genital tract than in blood, but there has been little research describing concentrations of NRTI drugs in cervicovaginal fluid.
Investigators from the US state of Rhode Island therefore obtained paired blood and cervicovaginal fluid samples from HIV-positive women receiving antiretroviral therapy. All the women had a blood viral load below 80 copies/ml for at least six months.
A total of 34 women were included in the study, median age was 44 years, and 44% of the patients were black. CD4 cell counts were between 200 – 500 cells/mm3 in 20 patients (59%), and twelve individuals (35%) had a CD4 cell count above 500 cells/mm3.
Nearly all the patients had antibodies to the genital herpes virus, HSV-2, and all 34 women had test results that were positive for bacterial vaginosis at baseline.
Antiretroviral therapy consisted of two NRTIs with either an NNRTI or protease inhibitor in 30 women, with three of the women taking a three or four drug NRTI combination and one woman a regimen that did not include any NRTIs.
All but three women were receiving either therapy that included 3TC or tenofovoir.
A total of four paired blood and cervicovaginal fluid samples were obtained from the women over a twelve month period. There was considerable divergence in concentrations of drugs in the blood and the genital tract.
Concentrations of tenofovir in cervicovaginal fluid were five times those in the blood. High concentrations of 3TC in cervicovaginal fluids were also observed, with levels of the drug in the genital tract being three times higher than those seen in the blood. In addition, levels of FTC (emtricitabine, Emtriva) were 50% higher in the genital tract than blood and those of ddI some nine times higher.
But concentrations in the genital tract of efavirenz (Sustiva) were only 1% of those achieved in the blood, and concentrations of protease inhibitors in cervicovaginal fluid were between 3% - 33% of those in the blood.
Nevertheless, good suppression of viral load in the genital tract was maintained by all women with good adherence to antiretroviral therapy. Seven women experienced a rebound in their blood viral load between 100 – 1400 copies/ml during the study. But in only one woman did viral load become detectable in the genital tract. This patient was noted for her poor adherence to her anti-HIV treatment and had extremely undetectable concentrations of some antiretroviral drugs in both her blood and cervicovaginal fluids.
“This study examined the concentrations of components of [antiretroviral therapy] in the cervicovaginal fluid of women who had achieved excellent viral suppression in blood plasma and sought to correlate local drug concentrations with subsequent virologic rebound,” write the investigators.
They emphasise the particularly good penetration of 3TC and tenofovir into the genital tract and suggest “the excellent accumulation of these agents in the cervicovaginal fluid may be beneficial for the prevention of HIV transmission during [antiretroviral therapy] and for pre- and post-sexual exposure antiretroviral prophylaxis.”
Although both NNRTIs and protease inhibitors had poor concentrations in the genital tract compared to blood “sustained suppression of HIV RNA levels were observed in the genital tract compartment.”
The investigators suggest that their findings should be interpreted with caution, particularly given the small number of patients in the study.
Kwara A et al. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis 46: (Online edition), 2008.