HIV Sexual Transmission Factors: viral load, circumcision:
Load and Heterosexual Transmission of Human Immunodeficiency Virus Type 1
(N Engl J Med 2000;342:921-9)
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
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.
were no seroconversions among the 50 circumcised male partners
strong association between increasing serum HIV-1 RNA levels and an increasing risk of heterosexual transmission of HIV-1
were no instances of transmissions by HIV-positive subjects with undetectable
viral loads or with serum HIV-1 RNA levels of less than 1500 copies per
persons with a genital discharge appear to have increased HIV-1 RNA levels in genital secretions
findings raise 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
Background and Methods.
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
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).
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.
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
(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.
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.
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.
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.
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.
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.