Drug activity in the genital tract of men

Although most studies show that the majority of men treated with antiretroviral drugs demonstrated parallel declines in plasma and seminal viral load, all studies have shown considerable individual variation in responses.

The following patterns have been observed:

• Viral load becomes undetectable in plasma weeks or months before doing so in semen.
• Viral load becomes undetectable in semen but not in plasma.
• Plasma viral load rebounds after a period of undetectability but seminal viral load remains undetectable.
• Discrepancies between the emergence of resistance in the blood and semen.

In the first case, prolonged HIV production in the genital tract may be explained by the fact that long-lived cells which have been infected by HIV continue to pump out virus copies because anti-HIV drugs cannot adequately penetrate these particular cells. Another explanation might be that virus production continues because latently infected cells are triggered into virus production by the presence of infections or inflammation.

One particular infection that has synergy with HIV infectivity is genital herpes (HSV2). The presence of (often asymptomatic) herpes infection in the genital tract both increases the amount of HIV produced by infected cells in the HIV-positive person and makes cells in the genital and anal tracts of the HIV-negative person more susceptible to infection. It does this both by directly affecting the genetic turnover of HIV and by stimulating the release of inflammatory cytokines like IL-4 which make cells both more expressive of, and more receptive to, HIV. In vivo studies report that aciclovir treatment can produce a survival benefit in HIV-1-infected patients and that recurrent genital herpes appears to be linked to HIV-1 transmission by both boosting plasma retroviral load and providing a portal of entry and exit for HIV-1 (reviewed in Palu 2001).

However, even when HIV is `undetectable' by bDNA testing in semen, this does not mean that it has disappeared. The viral load test cannot detect viral load below 1,000 copies in semen, and more sensitive tests must be used to establish whether semen still contains infectious HIV. These tests look for HIV's DNA. The presence of HIV DNA suggests the presence of actively replicating infectious HIV.

One small study found that three out of eleven patients on antiretroviral therapy with undetectable viral load in semen still had detectable HIV DNA when more sensitive tests were conducted.

A larger study of over 100 men on treatment examined blood and semen samples for HIV RNA and DNA. Only two treated men (2%) had HIV RNA in their semen in comparison to 67% of untreated controls. Of the 53 treated men tested for cell-associated HIV DNA, nine had detectable HIV DNA in contrast to 21 of 55 untreated controls. These statistically significant differences suggest that antiretroviral therapy does reduce the amount of HIV in semen. However, some HIV may remain in semen and HIV transmission through the exchange of sexual fluids remains a possibility despite treatment (Vernazza 1998).

Another study of 52 HIV-infected men has found a substantial minority do not have a correlation between seminal and blood plasma viral load. Twenty men had seminal viral load equivalent or higher than their blood plasma viral load (Tachet 1999).

Whilst some doctors have argued that reducing viral load in semen will have a beneficial effect on transmission rates, others caution that this is not yet proven (Vernazza; Albrecht).

A 58 week study of 11 men taking antiretroviral therapy found that different viral variants emerged in plasma and semen in seven out of eight men in whom drug resistance mutations could be identified. These findings suggest that different forms of drug pressure are operating in the plasma and the male genital tract, and lends some support to the view that protease inhibitors do not penetrate the male genital tract in high enough concentrations to prevent the development of resistance (Eron). Analysis of mutations in HIV taken from semen and blood has led some researchers to propose that a separate seminal HIV reservoir exists in some men.

The largest study to date, in 85 Brazilian men who had been followed for at least six months after starting antiretroviral therapy, found that 74% of individuals had detectable HIV in their semen at baseline. All had undetectable viral load within four months of starting therapy, but by month 6, 44% had experienced viral load rebound in plasma, compared to only 25% in semen (Barroso).

Poor penetration of protease inhibitors into the genital tract has also been reported. A study of drug levels in eight patients receiving ritonavir, saquinavir and stavudine (d4T) showed undetectable levels of saquinavir in semen despite high plasma levels in some patients, and sub-therapeutic levels of ritonavir (Taylor). Protease levels in the semen were generally less than 5% of the levels attained in the blood. Despite the poor penetration, viral load was reduced to undetectable levels in the semen and blood plasma after six months of treatment.

Sub-therapeutic levels might encourage the development and transmission of drug-resistant virus. Poor penetration of PIs is probably due to the protein binding of protease inhibitors and the high protein content of semen, or to the low levels of polyglycoprotein (Pgp), a substance which pumps protease inhibitor molecules out of cells. Pgp is present at very low levels in cells of the brain and testes.

Other conditions such as urethritis (inflammation of the urethra) may be associated with detectable HIV RNA in semen. One study of seven HIV-positive men found that seven had asymptomatic urethritis, four of whom had detectable virus in their semen, despite anti-HIV treatment (Winter).

A recent study found that in the majority of gay men the presence of chlamydia or NSU did not result in seminal viral load becoming detectable. However four men in the study had gonorrhoea and all had detectable viral loads, possibly because gonorrhoea is particularly inflammatory. It may also be worth noting that the study found that although the majority of men with no sexually transmitted infections and an undetectable plasma viral load also had an undetectable seminal viral load, this was not always the case (Sadiq).

Drug activity in the genital tract in women

Several large studies (52, 55 and 112 women tested) have found a strong association between the level of viral load in blood and the level of viral load in cervicovaginal fluid (Hart, Hoesley, Cuuvin). The initiation of antiretroviral therapy significantly reduced HIV RNA in vaginal fluid in one study.

However, there is some evidence that antiretroviral therapy may have discrepant effects on blood and on cervicovaginal fluid, especially when a genital infection is present. An American study of 11 women on antiretroviral therapy showed that viral load in vaginal fluid was significantly higher. The presence of genital tract infections such as thrush or inflammatory lesions of the vulva or cervix was predictive a discrepant response to anti-HIV treatment. The authors of the study have noted that their results should be treated with caution due to the small sample size and the fact that none of the women were receiving protease inhibitor treatment (Stephens).

Another small study has found that HIV in blood and in cervicovaginal fluid (CVF) is genetically distinct, suggesting that HIV in CVF is being produced by activation of local immune cells (Subbarao).