Viral Load and Heterosexual Transmission of Human Immunodeficiency Virus Type 1
Thomas C. Quinn, M.D., Maria J. Wawer, M.D., Nelson Sewankambo, M.B., David Serwadda, M.B., Chuanjun Li, M.D., Fred Wabwire-Mangen, Ph.D., Mary O. Meehan, B.S., Thomas Lutalo, M.A., Ronald H. Gray, M.D., for The Rakai Project Study Group
Background and Methods We examined the influence of viral loadin relation to other risk factors for the heterosexual transmissionof human immunodeficiency virus type 1 (HIV-1). In a community-basedstudy of 15,127 persons in a rural district of Uganda, we identified415 couples in which one partner was HIV-1–positive andone was initially HIV-1–negative and followed them prospectivelyfor up to 30 months. The incidence of HIV-1 infection per 100person-years among the initially seronegative partners was examinedin 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-femaletransmission was not significantly different from the rate offemale-to-male transmission (12.0 per 100 person-years vs. 11.6per 100 person-years). The incidence of seroconversion was highestamong the partners who were 15 to 19 years of age (15.3 per100 person-years). The incidence was 16.7 per 100 person-yearsamong 137 uncircumcised male partners, whereas there were noseroconversions among the 50 circumcised male partners (P<0.001).The mean serum HIV-1 RNA level was significantly higher amongHIV-1–positive subjects whose partners seroconverted thanamong those whose partners did not seroconvert (90,254 copiesper milliliter vs. 38,029 copies per milliliter, P=0.01). Therewere no instances of transmission among the 51 subjects withserum HIV-1 RNA levels of less than 1500 copies per milliliter;there was a significant dose–response relation of increasedtransmission with increasing viral load. In multivariate analysesof log-transformed HIV-1 RNA levels, each log increment in theviral 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 riskof heterosexual transmission of HIV-1, and transmission is rareamong persons with levels of less than 1500 copies of HIV-1RNA per milliliter.
In sub-Saharan Africa, the predominant mode of transmissionof human immunodeficiency virus type 1 (HIV-1) is through heterosexualcontact, and the rate of transmission by this means is increasingthroughout Asia and in many industrialized countries.1,2 A widevariety of behavioral and biologic risk factors are associatedwith the risk of transmission, including the frequency3,4,5and types6 of sexual contact, the use or nonuse of condoms,5,7immunologic status,8 and the presence or absence of the acquiredimmunodeficiency syndrome (AIDS),8 circumcision (in men),9,10,11and sexually transmitted diseases.6,12,13 Other potential factorsinclude plasma HIV-1 RNA levels,14,15,16,17 the presence orabsence of chemokine receptors,18,19 and the use or nonuse ofantiretroviral therapy.20 Improved understanding of the wayin which these factors influence both the infectiousness ofand the susceptibility to HIV-1 could facilitate efforts toprevent transmission of the virus.
To delineate the risk factors associated with heterosexual transmissionof HIV-1 more clearly, we prospectively followed couples discordantfor HIV-1 status in stable sexual relationships in a group ofcommunities with a high prevalence of infection with HIV-1 (16.1percent), mainly subtypes A and D. We were able to identifythese couples retrospectively from a community-based trial of15,127 persons residing in the rural district of Rakai, Uganda.21We analyzed sociodemographic, behavioral, and biologic factors,with particular emphasis on the effects of serum viral loadon the risk of heterosexual transmission of HIV-1.
Methods
Study Population
The Sexually Transmitted Diseases Control for AIDS PreventionStudy, a community-based randomized trial, was conducted inRakai between November 1994 and October 1998. The design andresults of the study have been reported previously.21 In brief,rural communities on secondary roads were aggregated into 10clusters; 5 clusters were randomly assigned to receive interventionfor sexually transmitted diseases, and 5 clusters were randomlyassigned to a control group. Five community-based surveys wereconducted at intervals of 10 months.
Eligible persons were read a consent form that explained thestudy and its potential risks and benefits, and they were informedof their rights to decline all or part of the study activitieswithout loss of access to clinical and educational services.The trial was approved by the AIDS Research Subcommittee ofthe Uganda National Council for Science and Technology, thehuman-subjects review boards of Columbia University and JohnsHopkins University, and the National Institutes of Health Officefor Protection from Research Risk. Safety was assessed by anindependent data safety and monitoring board.
Subjects in both groups received identical, intensive instructionon the prevention of HIV-1 infection and condom use and wereoffered free condoms and voluntary, confidential serologic testingfor HIV-1 and counseling by trained project counselors. Sincethis was a community-based trial that enrolled all consentingadults, the identification of couples within the general populationwas done only retrospectively. Hence, our study differs fromother investigations that selectively identified and followedHIV-1–discordant couples. During our study, individualand couples counseling was continually offered to all subjects,who were strongly encouraged to make use of this service, asrecommended by the AIDS Control Programme of the Ugandan Ministryof Health.22 All subjects were also strongly encouraged to obtainthe results of their tests for HIV-1 and to share the resultswith their partners, in accordance with the testing policy ofthe AIDS Control Programme.22 This policy explicitly statesthat "it is the right of the patient to decide who else to informabout the results" and thus precludes the "revealing [of the]results to sexual partners or spouses."22 The policy also specifiesthat "medical personnel and anybody who has, during the courseof their work, access to confidential information about thepatient, does not divulge this information to third partieswho are not directly involved in the care of the patient" andthat, "because of the stigma and discrimination arising fromHIV infection and AIDS, it is more important that everybodyadheres strictly to this principle."22
Free condoms were made continuously available to the entirecommunity. At each visit, health care was provided by RakaiProject mobile clinics, and subjects were advised to seek carein government clinics if they had symptoms that suggested theacquisition of sexually transmitted diseases between surveyvisits.
Subjects who were legally married or in consensual union, definedas a culturally accepted long-term sexual relationship, wereasked to provide the name and address of the spouse or consensualpartner. Such information was obtained for 75 percent of alleligible couples. During the first four surveys, we were ableto identify 415 couples that were discordant for HIV-1 and thatwere together during the interval in which there was a riskof seroconversion. Rates of transmission and acquisition ofHIV-1 were assessed in these couples.
Interviews and Tests
At base line and at each follow-up visit, subjects were interviewedseparately and in private by same-sex interviewers to ascertaintheir sociodemographic characteristics; sexual behavior (thenumber of sexual partners in the past year and condom use);history of travel outside of the district; health history, includingsymptoms of genital ulcer disease, genital discharge, and dysuriathat were present at the time of each interview and during theperiod between surveys; history of and treatment for sexuallytransmitted diseases; and the presence of AIDS-defining symptomsor conditions, according to the World Health Organization (WHO)criteria for a presumptive diagnosis.23 The circumcision statusof the male subjects was ascertained.
At base line and at each follow-up visit, all subjects wereasked to provide a venous blood sample and a 10-ml first-catchurine sample, and the female subjects provided self-collectedvaginal swabs; compliance was over 90 percent. Venous bloodwas tested for HIV-1 with two enzyme immunoassays (VironostikaHIV-1, Organon Teknika, Charlotte, N.C., and Cambridge Biotech,Worcester, Mass.), with confirmation of discordant results byWestern blotting (HIV-1 Western Blot, BioMerieux-Vitek, St.Louis). Syphilis was diagnosed with use of a commercial test(Toluidine Red Unheated Serum Test, New Horizons, Columbia,Md.), and positive samples were confirmed by treponemal-specifictests (TPHA Sera-Tek, Rujibero, Tokyo, Japan, or FTA-ABS IFAtest system, Zeus Scientific, Raritan, N.J.). Urine sampleswere tested by a ligase chain reaction for Neisseria gonorrhoeaeand Chlamydia trachomatis (LCx Probe System, Abbott Laboratories,Abbott Park, Ill.) in a subgroup of subjects. Among women, self-collectedvaginal swabs were cultured for Trichomonas vaginalis (InPouchTV culture, BioMed Diagnostics, San Jose, Calif.) and examinedmorphologically for bacterial vaginosis with the use of Gram'sstaining.
The results of measurements of serum HIV-1 RNA were not availableduring the study. Archived serum samples from the couples weretested in batches approximately one year after the completionof the trial. Serum levels of HIV-1 RNA were quantified by areverse-transcriptase–polymerase-chain-reaction assay(Amplicor HIV-1 Monitor 1.5 assay, Roche Molecular Systems,Branchburg, N.J.), as previously described.24 This assay hasbeen shown to quantitate all subtypes of HIV-1 reliably, includingsubtypes A and D, which are present in Uganda.25 The limit ofdetection was 400 copies of HIV-1 RNA per milliliter, and sampleswith values below this limit were assigned a value of 399 permilliliter for the purpose of analysis.
Among couples in which the HIV-1–negative partner seroconverted,the HIV-1 RNA assay was performed on the serum sample obtainedfrom the HIV-1–positive index partner at the study visitbefore the 10-month interval in which there was a risk of seroconversion(i.e., an average of 4 to 5 months before probable seroconversion).Couples in which there was no seroconversion were matched withcouples with seroconversion according to the sex and age (withinfive years) of the HIV-1–positive and HIV-1–negativepartners and the timing of the follow-up visit. For the couplesthat remained discordant, we selected from the HIV-1–positivepartner the serum sample that was obtained closest in time tothat of the matched seroconverting couple. Thus, the assayswere frequency-matched according to sex, age, and the time atwhich samples were obtained in the case of both HIV-1–positivepartners who transmitted the virus and those who did not.
Antiretroviral drugs are not available in rural Uganda. Consequently,the HIV-1 RNA levels were not influenced by the use of antiretroviraldrugs.
Statistical Analysis
Descriptive analyses were conducted separately according toage and sex and the characteristics of the HIV-1–positiveand HIV-1–negative partners. The presence or absence ofsexually transmitted diseases was determined at the visit beforeand the one following the interval in which there was a riskof seroconversion, whereas information on behavior and symptomsof sexually transmitted disease during that interval were determinedat the visit after the interval. At each visit, subjects wereasked about current symptoms. The incidence of HIV-1 was estimatedper 100 person-years in HIV-1–negative subjects and wasbased on the assumption that seroconversion occurred at themidpoint of the 10-month follow-up interval. The incidence wastabulated separately according to sociodemographic characteristics,behavior, and symptoms and diagnoses of sexually transmitteddiseases in HIV-1–positive partners (i.e., to indicatethe risk of transmission) and in HIV-1–negative partners(i.e., to indicate the risk of acquisition).
Tests of statistical significance included the 95 percent confidenceintervals of the unadjusted rate ratios, two-sided P valuesbased on chi-square tests or the chi-square test for trend,and Fisher's exact test.26 Formal adjustments for multiple comparisonswere not performed for associations based on a priori hypotheses(e.g., that transmission rates would increase with higher serumHIV-1 RNA loads, younger age, the absence of circumcision, andthe presence of sexually transmitted diseases or their symptoms).In addition, we hypothesized that viral load would be higheramong subjects who transmitted the disease to their partnersthan among those who did not. Mean and median viral loads wereestimated on the basis of untransformed data and on data transformedto the base-10 logarithm. Viral loads were analyzed for theHIV-1–positive partners who transmitted the virus andfor those who did not transmit the virus, and as well as accordingto age and sex. The t-test was used to compare mean viral loads.26
Multivariate adjusted rate ratios for the risk of seroconversionwere estimated with the use of Poisson regression analysis.27The viral load was the independent variable of interest andwas assessed in separate models in which the actual viral load(copies per milliliter) was included as a categorical variableand the log-transformed viral load was included as a continuousvariable. For the categorical variable, a serum HIV-1 RNA levelof less than 3500 copies per milliliter was used as the referencecategory because there were no instances of seroconversion ofHIV-1–negative subjects whose partners had HIV-1 RNA levelsof less than 1500 copies per milliliter, and the rate ratiosof HIV-1 seroconversion were estimated for viral loads of 3500to 9999 copies per milliliter, 10,000 to 49,999 copies per milliliter,and 50,000 or more copies per milliliter. All models includedterms for age (15 to 19, 20 to 29, 30 to 39, and 40 to 59 years)and for the sex of HIV-1–positive partners. The numberof sexual partners in the past year (one vs. two or more), useor nonuse of condoms, circumcision or noncircumcision of themale partner, presence or absence of symptoms of sexually transmitteddiseases (genital ulcer disease, genital discharge, and dysuria),and presence or absence of sexually transmitted diseases (syphilis,gonorrhea, and chlamydia in both sexes and trichomonas and bacterialvaginosis in women) were also assessed. Separate models werefitted for the characteristics of the HIV-1–positive partnersand the HIV-1–negative partners.
Results
Demographic Characteristics and Incidence of HIV-1
A total of 415 couples discordant for HIV-1 were enrolled betweenthe first and the fourth survey and followed for a period ofup to 30 months (median follow-up, 22.5). The male partner wasinfected with HIV-1 at base line in 228 of these 415 couples(55 percent), and the female partner was infected in 187 (45percent) (Table 1). Ninety (22 percent) of the HIV-1–negativepartners seroconverted during the course of the study, for anoverall incidence of 11.8 per 100 person-years. Fifty (56 percent)of the partners who seroconverted were female, and 40 (44 percent)were male. The rate of transmission from male partners to femalepartners was not significantly different from the rate of transmissionfrom female partners to male partners (12.0 per 100 person-yearsvs. 11.6 per 100 person-years). The median age at enrollmentwas 30.3 years among HIV-1–negative partners and 29.4years among HIV-1–positive partners (P> 0.05). Thehighest incidence of seroconversion was among couples in theage group of 15 to 19 years (Table 1). The incidence declinedwith the age of both HIV-1–negative and HIV-1–positivepartners, but these trends were not statistically significant(P>0.05).
Table 1. Rates of Acquisition and Transmission of HIV-1 According to Age and Sex.
Characteristics of HIV-1–Negative Partners Associated with the Acquisition of Infection
On bivariate analysis, there were no significant differencesin the risk of infection among HIV-1–negative partnersaccording to the level of formal education, history of traveloutside the district within the previous year, the number ofsexual partners within the past year (one vs. two or more),or condom use or nonuse. However, 364 of 407 HIV-1–negativepartners for whom information was available (89 percent) neverused condoms (Table 2). The rate of seroconversion among uncircumcisedmale subjects was 16.7 per 100 person-years, whereas no seroconversionsoccurred among circumcised male subjects (P< 0.001). Therewere no significant differences in the rate of acquisition ofHIV-1 infection according to either the presence or absenceof symptoms of sexually transmitted diseases (Table 2) or thepresence or absence of syphilis, gonorrhea, chlamydia, trichomonas,and bacterial vaginosis (data not shown).
Table 2. Rates of Acquisition and Transmission of HIV-1, According to the Characteristics of the Initially HIV-1–Negative Partners and the HIV-1–Positive Partners.
Characteristics of HIV-1–Positive Partners Associated with the Transmission of Infection
Transmission rates were not significantly affected by the levelof formal education, travel history, the number of sexual partnerswithin the preceding year, or condom use or nonuse. Uncircumcisedmale subjects had a higher rate of transmission than circumcisedmale subjects (13.2 per 100 person-years vs. 5.2 per 100 person-years),but this difference was not statistically significant (P=0.17).On bivariate analysis, the laboratory diagnosis of sexuallytransmitted diseases (data not shown) or genital ulcer diseasedid not significantly increase the rate of transmission. However,a history of genital discharge or dysuria in the HIV-1–positivepartner was associated with a significantly increased transmissionrate (P<0.05). The presence of AIDS-defining symptoms orsigns was also associated with a significantly increased rateof transmission (27.3 per 100 person-years vs. 11.4 per 100person-years, P<0.05). However, only 14 of 415 HIV-1–positivesubjects (3 percent) met the WHO criteria for AIDS.
HIV-1 RNA Levels and the Risk of Transmission
Of the 415 seropositive partners, 364 (88 percent) had detectableserum levels of HIV-1 RNA. The mean serum level of HIV-1 RNAamong the 228 HIV-1–positive men was 59,591 copies permilliliter (median, 15,649) and was significantly higher thanthe mean level of 36,875 copies per milliliter among the 187HIV-1–positive women (median, 9655; P=0.03). When thelog-transformed values were used, the mean (±SD) valuewas 4.11±0.86 log copies of HIV-1 RNA among the men and3.90±0.83 log copies of HIV-1 RNA among the women (P=0.008)(Table 3). Among couples in which the initially HIV-1–negativepartner seroconverted, the mean serum HIV-1 RNA level of theHIV-1–positive partner was significantly higher than thatof the HIV-1–positive partner in couples in which theHIV-1–negative partner remained seronegative (mean, 90,254copies per milliliter vs. 38,029 copies per milliliter; P=0.01).When these two subgroups were analyzed according to sex, thelog-transformed values were significantly higher among maleand female subjects whose partners seroconverted than amongmale and female subjects whose partners did not seroconvert(P=0.001) (Table 3).
There was a significant dose–response effect with respectto both male-to-female transmission and female-to-male transmission(P<0.001) (Figure 1). The rate of transmission was zero amongthe 51 couples in which the HIV-1–positive partner hadundetectable serum levels of HIV-1 RNA or less than 1500 copiesper milliliter. Among HIV-1–positive partners with serumHIV-1 RNA levels of less than 3500 copies per milliliter, therate of transmission was 2.2 per 100 person-years, and the ratesprogressively increased with increasing viral loads, to a maximumof 23.0 per 100 person-years at a level of 50,000 or more copiesper milliliter. It is noteworthy that among the 90 instancesof transmission, 5.6 percent occurred among couples in whichthe HIV-1–positive partner had serum HIV-1 RNA levelsof 400 to 3499 copies per milliliter, 17.7 percent among couplesin which the seropositive partner had levels of 3500 to 9999copies per milliliter, 40.0 percent among couples in which theseropositive partner had levels of 10,000 to 49,999 copies permilliliter, and 36.7 percent among couples in which the seropositivepartner had levels of 50,000 or more copies per milliliter.There was no significant difference between male-to-female andfemale-to-male transmission rates after the results were adjustedfor viral load (P=0.76), and there were no consistent differencesbetween male-to-female or female-to-male transmission rateswithin strata of viral load (Figure 1).
Figure 1. Mean (+SE) Rate of Heterosexual Transmission of HIV-1 among 415 Couples, According to the Sex and the Serum HIV-1 RNA Level of the HIV-1–Positive Partner.
At base line, among the 415 couples, 228 male partners and 187 female partners were HIV-1–positive. The limit of detection of the assay was 400 HIV-1 RNA copies per milliliter. For partners with fewer than 400 HIV-1 RNA copies per milliliter, there were zero transmissions.
Results of Multivariate Logistic-Regression Analysis
We constructed several Poisson regression models, the resultsof which are summarized in Table 4. Viral load was the variablemost strongly predictive of the risk of transmission. When viralload was measured as a categorical variable, with HIV-1–positivepartners with serum HIV-1 RNA levels of less than 3500 copiesper milliliter as the reference group, the rate ratio of therisk of transmission increased from 5.80 (95 percent confidenceinterval, 2.26 to 17.80) for HIV-1–positive subjects withHIV-1 RNA levels of 3500 to 9999 copies per milliliter to 11.87(95 percent confidence interval, 5.02 to 34.88) for seropositivesubjects with 50,000 or more copies per milliliter. When viralload was measured as a continuous variable, the rate ratio forthe risk of transmission associated with each log incrementin viral load was 2.45 (95 percent confidence interval, 1.85to 3.26).
Table 4. Adjusted Rate Ratios of the Risk of Transmission and Acquisition of HIV-1.
As compared with the risk of transmission among HIV-1–positivepartners who were 15 to 19 years of age, the risk of transmissiondecreased with older age, after adjustment for viral load, andthis decrease was significant for those who were 30 to 39 yearsof age (rate ratio, 0.32) and those who were 40 to 59 yearsof age (rate ratio, 0.27). The interaction between age and log-transformedviral load was not statistically significant (P=0.06). The riskof transmission was lower among circumcised male subjects thanamong uncircumcised male subjects, but this difference was notsignificant (rate ratio, 0.41; 95 percent confidence interval,0.10 to 1.14).
The risk of infection increased as the HIV-1–infectedpartner's viral load increased and decreased with age amongHIV-1–negative partners. The risk of infection was zeroamong the 50 HIV-1–negative circumcised male subjects.A history of multiple sexual partners, symptoms of sexuallytransmitted diseases, or the laboratory diagnosis of sexuallytransmitted diseases had no significant effect on the risk ofHIV-1 infection.
Discussion
Prospective studies of HIV-1–discordant couples provideimportant information on the efficiency of transmission andthe biologic and behavioral variables that influence the infectiousnessof and susceptibility to HIV-1. Our study of heterosexual transmissionamong sexual partners was a community-based study in which allconsenting couples, whether discordant for HIV-1 or not, wereprospectively followed to evaluate the risk of transmissionin relation to viral load and other characteristics. Our studysample is representative of the general population in this ruralarea of Uganda.
All participants were asked whether they wanted to know theresults of their HIV-1 tests, all were offered counseling aftertesting and free condoms in the privacy of their own homes,and all were told about safe-sex practices. Couples counselingwas also offered to the entire community, and all subjects werestrongly encouraged to share the results of testing with theirpartners. Although the rate of condom use remained low in theentire study population, as has been the case in other studiesin Uganda,28 we did observe an increase in current condom useover the four-year study, from 4.4 percent to 7.4 percent asreported by women and from 9.9 percent to 16.9 percent as reportedby men; these values represent some of the highest rates ofuse in rural sub-Saharan Africa. However, with this rate ofcondom use, HIV-1 was transmitted to 90 of the 415 initiallyHIV-1–negative partners, for an overall incidence of 11.8per 100 person-years. This was significantly higher than theincidence of 1.0 per 100 person-years reported among couplesin which both members were initially seronegative.21
The major finding of this study was the strong association betweenincreasing serum HIV-1 RNA levels and an increasing risk ofheterosexual transmission of HIV-1. In a finding similar tothose of studies that found that the risk of perinatal HIV-1infection is associated with the maternal viral load,24,29,30,31,32we found a dose–response effect: the rate of transmissionincreased from 2.2 per 100 person-years to 23.0 per 100 person-yearsas the serum HIV-1 RNA level increased from less than 3500 copiesper milliliter to 50,000 or more copies per milliliter (adjustedrate ratio, 11.87). In multivariate analyses, the serum HIV-1RNA level was the main predictor of the risk of transmission(Table 4). Each log increase in viral load was associated withan increase by a factor of 2.45 in the risk of transmission.There were no instances of transmissions by seropositive subjectswith undetectable viral loads or with serum HIV-1 RNA levelsof less than 1500 copies per milliliter. This finding raisesthe possibility that reductions in viral load brought aboutby the use of antiretroviral drugs could potentially reducethe rate of transmission in this population. Such reductionsin transmission have been documented in studies of perinataltransmission,30,32,33 but not in studies of sexual transmission.Further studies measuring the effects of antiretroviral drugson sexual transmission are urgently needed.
Several studies have shown a good correlation between peripheral-bloodviral load and viral load in seminal plasma34 and cervical secretions,35,36and viral loads in genital secretions appear to fall in concertwith the declines in peripheral-blood viral load after combinationtherapy.20,34,37 However, the rate of transmission of HIV-1was not assessed in these studies, and despite reductions inperipheral-blood and seminal plasma viral load, integrated viralDNA is still present in seminal cells, and virus can be recoveredin vitro.38,39,40 However, it is apparent from our results thatthe rate of transmission is markedly reduced among persons withvery low serum viral loads.
In multivariate analyses, we did not find a significant associationbetween the risk of HIV-1 transmission and the presence of sexuallytransmitted diseases or symptoms of sexually transmitted diseasesin HIV-1–positive partners, or between an increased susceptibilityto infection and sexually transmitted diseases among HIV-1–negativepartners. However, genital discharge and dysuria in the seropositivepartner were significant in the unadjusted analysis. This lastfinding, even though not significant in the multivariate analysis,is compatible with findings from other studies in which personswith a genital discharge had increased HIV-1 RNA levels in genitalsecretions.41,42
In analyses of the risk of transmission according to male orfemale sex, we found no significant difference in incidencebetween female-to-male transmission and male-to-female transmission.The rate in each group was about 12 per 100 person-years. Foreach category of viral load, the rates of transmission weresimilar in both sexes, and these results reflect the nearlyequal distribution of HIV-1 infection between men and womenin this community and in most other parts of Africa.1,43 Thetransmission rates reported here reflect a combination of theprobability of transmission per sexual act, the frequency ofsexual contact, viral shedding in the genital tract as influencedby the presence of concurrent genital tract infections, andother variables.
Despite similarities in transmission rates between the sexesat each level of viral load, seropositive female subjects didhave significantly lower log-transformed mean viral loads thanmale subjects, and this sex-specific difference was greatestamong the subjects who transmitted the virus to their partners(mean log-transformed viral load, 4.30 among seropositive femalesubjects and 4.62 among seropositive male subjects; P=0.015).These data are consistent with recent reports that female subjectshave lower viral loads than male subjects matched with themfor age and CD4 count, despite the fact that they had similarrates of progression and similar decreases in the CD4 count.44,45The mechanisms for these sex-based differences in viral loadare unclear.
An additional finding in our study was that circumcision wasprotective against HIV-1 infection, with no infections occurringamong 50 circumcised HIV-1–negative male subjects, ascompared with 40 infections among 137 HIV-1–negative uncircumcisedmale subjects. This finding suggests that male circumcisionmay reduce the risk of acquisition at all HIV-1 RNA levels.Studies among truck drivers, persons attending sexually transmitteddisease clinics, and prostitutes and their clients in Africahave shown that the absence of circumcision among men increasestheir risk of heterosexual acquisition of HIV-1,9,11,46 potentiallybecause of an association with an increased frequency of sexuallytransmitted diseases among uncircumcised men.11 This associationbetween male circumcision and a decreased risk of infectionwith HIV-1 may partially explain the low frequency of female-to-maletransmission in U.S. studies of HIV-1–discordant couples,47since over 70 percent of men in the United States are circumcised.
Limitations in the interpretation of our data include the factthat the interval between the measurement of the viral loadin the index subject and documentation of seroconversion inthe partner was 10 months, resulting in some imprecision asto the viral load at the time of transmission. Similarly, thediagnosis of sexually transmitted diseases was established atthe visit before and the visit after the end of the intervalin which there was a risk of seroconversion, which may havediluted the potential association between sexually transmitteddiseases and the risk of transmission of HIV-1. However, dataon symptoms of sexually transmitted diseases were availablefor the entire interval in which there was a risk of seroconversion,and serum viral load was a much stronger predictor of the riskof transmission than was the presence of such symptoms in eitherpartner.
Heterosexual transmission involves a complex interaction betweenbiologic and behavioral factors. Our data suggest that peripheral-bloodlevels of HIV-1 RNA contribute dramatically to the risk of heterosexualtransmission. Serum HIV-1 RNA levels below 1500 copies per milliliterwere not associated with transmission, whereas the risk of transmissionincreased substantially with increasing viral loads. These resultssuggest that research is urgently needed to develop and evaluatecost-effective methods, such as effective and inexpensive antiretroviraltherapy or vaccines, for reducing viral load in HIV-1–infectedpersons. Such measures, coupled with education about safe-sexpractices, condom use, HIV-1 testing and counseling, and controlof sexually transmitted diseases, could potentially reduce theinfectivity of and susceptibility to HIV-1 and prevent furthersexual transmission of the virus.
Supported by grants (R01 AI34826b and R01 AI34826S) from theNational Institute of Allergy and Infectious Diseases; by agrant (5P30HD06826) from National Institute of Child Healthand Human Development; and by the Rockefeller Foundation andthe World Bank Uganda Sexually Transmitted Infections Project.Some drugs and laboratory tests were provided by Pfizer, AbbottLaboratories, Roche Molecular Systems, and Calypte Biomedical.
We are indebted to S. Sempala (Uganda Virus Research Institute,Uganda Ministry of Health) for his support of the study; toSharon Hillier (University of Pittsburgh) for reviewing thevaginal swabs for bacterial vaginosis; to Patricia Buist foreditorial assistance; to Richard Kline, Christopher Urban, andDenise McNairn for performing viral-load assays; to all thestudy participants in Rakai District, Uganda, for their contributionsand support; and to Anthony Fauci, M.D., and Rodney Hoff, M.D.,for their helpful suggestions regarding the manuscript.
Source Information
From the National Institute of Allergy and Infectious Diseases, Bethesda, Md. (T.C.Q.); Johns Hopkins University, Baltimore (T.C.Q., C.L., R.H.G.); Columbia University, New York (M.J.W., M.O.M.); and the Faculty of Medicine, Makerere University, Kampala, Uganda (N.S., D.S., F.W.-M., T.L.).
Address reprint requests to Dr. Quinn at the Division of Infectious Diseases, Johns Hopkins University, 720 Rutland Ave., Ross 1159, Baltimore, MD 21205-2196.
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