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HIV viral load in Blood may not predict HIV shedding in vaginal secretions
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In HIV-infected women, the higher the plasma viral load, the more likely that HIV will be found in cervicovaginal secretions. However, in many women with undetectable plasma loads, HIV is still often found in such secretions, as reported in an article in the October 17 issue of AIDS (AIDS 2003;17:2169-2176) by , the lead author , Dr Jose Ramon (University of Bati, Italy).
The purpose of the study reported in AIDS by Dr Ramon is to evaluate the determinants of HIV-1 RNA shedding in cervicovaginal secretions and the effects of antiretroviral therapy in a group of infected women.
A total of 122 women HIV-infected for a mean of 51 months from whom paired peripheral blood and cervicovaginal lavage samples were available were enrolled in the study. HIV-1 RNA was quantified in the plasma and cell-free fraction of cervicovaginal lavages by an ultrsensitive test, the nucleic acid sequence-based amplification assay (lower limit of detection 80 copies/ml).
Dr Ramon found that 71% of the women had detectable viral load in the cervicovaginal lavage and this appeared to be correlated to plasma viral load and to the degree of immunodeficiency as expressed by the absolute number of CD4 cells.
Antiretroviral-treated patients had a lower risk of shedding the virus in the genital tract, but this association was limited to patients treated with highly active antiretroviral therapy (HAART). However, in 25% of women with undetectable plasma viral load, a genital shedding of the virus was demonstrated.
Dr Ramon concluded that plasma viral load may fail as a marker of infectivity of genital secretions. HAART treatment seems to be more efficacious in suppressing viral shedding at the genital level, and therefore one should be cautious when using this parameter to judge the risk of transmission. The female genital tract represents a distinct compartment for HIV-1 replication/evolution.
Background
Sexual intercourse, mainly heterosexual, is the predominant route for HIV-1 transmission worldwide and mother-to-child transmission has become an increasing public health problem in developing countries. In both cases, transmission is believed to occur through direct contact with the virus in the women's genital tract. As the inoculum size is an important determinant of virus transmission, the likelihood of perinatal and female-to-male transmission of HIV-1 is most likely associated with the amount of HIV in the cervix and vagina.
Studies regarding the presence, the amount and the determinants of HIV-1 RNA shedding in cervicovaginal secretions, in addition to the effects of antiretroviral therapy in its reduction, have thus important implications on the design of clinically based strategies for prevention of HIV transmission. Some reports suggest that factors altering the vaginal environment, such as certain genital infections, oral contraceptive use, and pregnancy are associated with an increased HIV-1 shedding; moreover, virological and immunological co-factors, for example, plasma viraemia or the degree of immunodeficiency, seem to influence such shedding. On the contrary, there is a lack of information concerning the effects of antiretroviral therapy on the presence of HIV in cervicovaginal secretions. Recently, two publications analysed cervicovaginal HIV-1 shedding and its relationship to antiretroviral treatment in a significant number of patients; however, ultrasensitive techniques were not utilized for the quantification of plasma and cervicovaginal loads in one study while a predominance of Latin-American and black women were enrolled among the patients in the other study, and thus it is not possible to draw definitive conclusions on this issue.
Herein, we report the results of a cross-sectional study in which the determinants of HIV-1 shedding in cervicovaginal secretions were analysed in a group of 122 infected Italian women with no clinical evidence of sexually transmitted diseases.
Author Comments
We observed that the presence of a genital HIV shedding was positively correlated with plasma viraemia. This accounts for its suggested role as a marker of transmission for plasma viral load, both in mother-to-child and heterosexual transmission of the virus; in fact, one would expect that detectable plasma loads would be associated with higher genital viral loads, a factor influencing the rate of transmission. However, the results presented herein indicate that the virological scenario in the blood and genital tract differ in a certain number of patients, suggesting that these sites may be considered as different compartments.
In fact, 25% of the women with undetectable virus in plasma enrolled in the study showed a cervicovaginal shedding of HIV-1; of these, four were naive to antiretrovirals and three were under non-HAART treatment. Fourteen women presented the opposite situation demonstrating detectable plasma viral load in the absence of genital shedding; the majority of these subjects were naive to treatment or under HAART therapy.
In addition, the present data indicate that different antiretroviral regimens may exert different effects on HIV shedding in cervicovaginal secretions. In fact, our results suggest that HAART treatment successfully reduces HIV viral load both in the plasma and vagina, although it appears to be more effective and rapid in the genital compartment. On the other hand, non-HAART treatment was found to be effective in reducing viral load in plasma but not at the cervicovaginal level. The interruption of antiviral therapy always resulted in detectable levels of HIV-1 RNA both in plasma and in vagina.
The role of high CD4 lymphocyte levels in reducing the viral load appeared to be more likely in the plasma than in the vagina. Therefore, a high CD4 cell count, even in the absence of plasma HIV-1 RNA (as shown in group C), does not necessarily imply the absence of HIV in the cervicovaginal secretions.
We also found that women who acquired the infection through sexual contact showed a significantly lower plasma viral load when compared to those who inject drugs; available data does not allow speculation as to whether this is due to diverse biological factors related to mode of HIV acquisition or to a diverse compartmentalization of the virus.
There is increasing evidence that a local HIV replication occurs within the female genital tract and that this site may be considered as a distinct compartment for viral replication/evolution. Data presented here support this hypothesis and deserve consideration. Antiretroviral treatment was shown to dramatically reduce both heterosexual and vertical viral transmission, probably via reduction of the viral load in the blood and genital secretions. It has been shown, however, that transmission may also occur even when antiretroviral agents are administered and a good response in the blood is achieved. This is most likely related to a lack of virological response at the mucosal level, that is, where transmission takes place.
More Study Findings
HIV-1 RNA was detected in 87/122 (71.3%) CVL samples; this occurred in 79.6% antiretroviral-naive women, in 100% of women interrupting treatment, in 78.9% of women under non-HAART regimens, and in 40% of women under HAART. As for plasma viraemia, both at univariate and multivariate analysis, the presence of detectable HIV-1 RNA in CVL was significantly associated with a decreased CD4 lymphocytes (OR, 0.79 per each 100 cells count more; P = 0.029), and with HAART treatment when compared to antiretroviral-naive subjects (OR, 0.07; P = 0.001); no association was related to clinical stage of the disease (AIDS versus non-AIDS) or the presence of Candida or Mycoplasma in vagina. However, contrary to that observed in the plasma, a detectable viral load in the vagina was not correlated with IDU, or the receiving of mono- or dual-antiretroviral treatment.
Women under HAART treatment were more likely to reach undetectable viral levels in the vagina, even if HIV RNA was detected in the plasma, whereas women under non-HAART treatment were more likely to shed HIV in genital secretions even in the absence of plasma viraemia. Similar results were found when the presence/absence of HIV-1 RNA in plasma and in the vaginal secretion was considered using two independent logistic regression models. An increased CD4 cell count and HAART treatment were significantly associated with non-detectable viral loads both in plasma and in vagina. Non-HAART treatment was significantly associated with HIV-1 RNA absence in plasma viraemia but not in vaginal secretions.
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