HIV Sexual Transmission Factors: viral load, circumcision:

Viral Load and Heterosexual Transmission of Human Immunodeficiency Virus Type 1
(N Engl J Med 2000;342:921-9)

Authors: Thomas C. Quinn, Maria J. Wawer, Nelson Sewankambo, David Serwadda, Chuanjun Li, Fred Wabwire-Mangen, Mary O. Meehan, Thomas Lutalo, Ronald H. Gray, for the Rakai Project Study Group

This study was reported at the Retrovirus Conference in Feb 2000, among others on perinatal and sexual transmission. See the NATAP web site Retrovirus Conferences reports to read these and other reports.

Brief Summary

Abstract
Background and Methods.

We examined the influence of viral load in relation to other risk factors for the heterosexual transmission of human immunodeficiency virus type 1 (HIV-1). In a community-based study of 15,127 persons in a rural district of Uganda, we identified 415 couples in which one partner was HIV-1-positive and one was initially HIV-1-negative and followed them prospectively for up to 30 months. The incidence of HIV-1 infection per 100 person-years among the initially seronegative partners was examined in relation to behavioral and biologic variables.

Results.
The male partner was HIV-1-positive in 228 couples, and the female partner was HIV-1-positive in 187 couples. Ninety of the 415 initially HIV-1-negative partners seroconverted (incidence, 11.8 per 100 person-years). The rate of male-to-female transmission was not significantly different from the rate of female-to-male transmission (12.0 per 100 person-years vs. 11.6 per 100 person-years). The incidence of seroconversion was highest among the partners who were 15 to 19 years of age (15.3 per 100 person-years). The incidence was 16.7 per 100 person-years among 137 uncircumcised male partners, whereas there were no seroconversions among the 50 circumcised male partners (P<0.001). The mean serum HIV-1 RNA level was significantly higher among HIV-1-positive subjects whose partners seroconverted than among those whose partners did not seroconvert (90,254 copies per milliliter vs. 38,029 copies per milliliter, P=0.01). There were no instances of transmission among the 51 subjects with serum HIV-1 RNA levels of less than 1500 copies per milliliter; there was a significant dose-response relation of increased transmission with increasing viral load. In multivariate analyses of log-transformed HIV-1 RNA levels, each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95 percent confidence interval, 1.85 to 3.26).

Conclusions.
The viral load is the chief predictor of the risk of heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter.   

Condom Use
Subjects in both groups received identical, intensive instruction on the prevention of HIV-1 infection and condom use and were offered free condoms and voluntary, confidential serologic testing for HIV-1 and counseling by trained project counselors

All subjects were also strongly encouraged to obtain the results of their tests for HIV-1 and to share the results with their partners, in accordance with the testing policy of the AIDS Control Programme

Free condoms were made continuously available to the entire community. At each visit, health care was provided by Rakai Project mobile clinics, and subjects were advised to seek care in government clinics if they had symptoms that suggested the acquisition of sexually transmitted diseases between survey visits.

Although the rate of condom use remained low in the entire study population, as has been the case in other studies in Uganda, we did observe an increase in current condom use over the four-year study, from 4.4 percent to 7.4 percent as reported by women and from 9.9 percent to 16.9 percent as reported by men; these values represent some of the highest rates of use in rural sub-Saharan Africa. However, with this rate of condom use, HIV-1 was transmitted to 90 of the 415 initially HIV-1-negative partners, for an overall incidence of 11.8 per 100 person-years. This was significantly higher than the incidence of 1.0 per 100 person-years reported among couples in which both members were initially seronegative

DISCUSSION (excerpted from the published article in the NEJM):
The major finding of this study was the strong association between increasing serum HIV-1 RNA levels and an increasing risk of heterosexual transmission of HIV-1. In a finding similar to those of studies that found that the risk of perinatal HIV-1 infection is associated with the maternal viral load, we found a dose-response effect: the rate of transmission increased from 2.2 per 100 person-years to 23.0 per 100 person-years as the serum HIV-1 RNA level increased from less than 3500 copies per milliliter to 50,000 or more copies per milliliter (adjusted rate  ratio, 11.87). In multivariate analyses, the serum HIV-1 RNA level was the main predictor of the risk of transmission. Each log increase in viral load was associated with an increase by a factor of 2.45 in the risk of transmission. There were no instances of transmissions by seropositive subjects with undetectable viral loads or with serum HIV-1 RNA levels of less than 1500 copies per milliliter. This finding raises the possibility that reductions in viral load brought about by the use of antiretroviral drugs could potentially reduce the rate of transmission in this population. Such reductions in transmission have been documented in studies of perinatal transmission, but not in studies of sexual transmission. Further studies measuring the effects of antiretroviral drugs on sexual transmission are urgently needed.

Several studies have shown a good correlation between peripheral-blood viral load and viral load in seminal plasma and cervical secretions, and viral loads in genital secretions appear to fall in concert with the declines in peripheral-blood viral load after combination therapy. However, the rate of transmission of HIV-1 was not assessed in these studies, and despite reductions in peripheral-blood and seminal plasma viral load, integrated viral DNA is still present in seminal cells, and virus can be recovered in vitro.  However, it is apparent from our results that the rate of transmission is markedly reduced among persons with very low serum viral loads.

Genital discharge and dysuria in the seropositive partner were significant in the unadjusted analysis. This last finding, even though not significant in the multivariate analysis, is compatible with findings from other studies in which persons with a genital discharge had increased HIV-1 RNA levels in genital secretions.

Limitations in the interpretation of our data include the fact that the interval between the measurement of the viral load in the index subject and documentation of seroconversion in the partner was 10 months, resulting in some imprecision as to the viral load at the time of transmission.

An additional finding in our study was that circumcision was protective against HIV-1 infection, with no infections occurring among 50 circumcised  HIV-1-negative male subjects, as compared with 40 infections among 137 HIV-1-negative uncircumcised male subjects. This finding suggests that male circumcision may reduce the risk of acquisition at all HIV-1 RNA levels. Studies among truck drivers, persons attending sexually transmitted disease clinics, and prostitutes and their clients in Africa have shown that the absence of circumcision among men increases their risk of heterosexual acquisition of HIV-1, potentially because of an association with an increased frequency of sexually transmitted diseases among uncircumcised men.  This association between male circumcision and a decreased risk of infection with HIV-1 may partially explain the low frequency of female-to-male transmission in U.S. studies of HIV-1-discordant couples, since over 70 percent of men in the United States are circumcised.

Heterosexual transmission involves a complex interaction between biologic and behavioral factors. Our data suggest that peripheral-blood levels of HIV-1 RNA contribute dramatically to the risk of heterosexual transmission. Serum HIV-1 RNA levels below 1500 copies per milliliter were not associated with transmission, whereas the risk of transmission increased substantially with increasing viral loads. These results suggest that research is urgently needed to develop and evaluate cost-effective methods, such as effective and inexpensive antiretroviral therapy or vaccines, for reducing viral load in HIV-1-infected persons. Such measures, coupled with education about safe-sex practices, condom use, HIV-1 testing and counseling, and control of sexually transmitted diseases, could potentially reduce the infectivity of and susceptibility to HIV-1 and prevent further sexual transmission of the virus.