Viral load and heterosexual transmission of human immunodeficiency virus type

V I R A L L OA D A N D H ET E R O S EXUA L T R A N S M I S S I O N O F H U M A N I M M U N O D E F I C I E N CY V I R U S T Y P E 1
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., AND RONALD H. GRAY, M.D., FOR THE RAKAI PROJECT STUDY GROUP ABSTRACT
N sub-Saharan Africa, the predominant mode Background and Methods
of transmission of human immunodeficiency vi- ence of viral load in relation to other risk factors for rus type 1 (HIV-1) is through heterosexual con- the heterosexual transmission of human immunode- tact, and the rate of transmission by this means ficiency virus type 1 (HIV-1). In a community-based is increasing throughout Asia and in many industri- study of 15,127 persons in a rural district of Uganda, alized countries.1,2 A wide variety of behavioral and we identified 415 couples in which one partner was biologic risk factors are associated with the risk of HIV-1–positive and one was initially HIV-1–negative transmission, including the frequency3-5 and types6 and followed them prospectively for up to 30 months.
of sexual contact, the use or nonuse of condoms,5,7 The incidence of HIV-1 infection per 100 person-years immunologic status,8 and the presence or absence of among the initially seronegative partners was exam- ined in relation to behavioral and biologic variables.
the acquired immunodeficiency syndrome (AIDS), Results
228 couples, and the female partner was HIV-1–pos- diseases.6,12,13 Other potential factors include plasma itive in 187 couples. Ninety of the 415 initially HIV-1– HIV-1 RNA levels,14-17 the presence or absence of negative partners seroconverted (incidence, 11.8 per chemokine receptors,18,19 and the use or nonuse of an- 100 person-years). The rate of male-to-female trans- tiretroviral therapy.20 Improved understanding of the mission was not significantly different from the rate way in which these factors influence both the infec- of female-to-male transmission (12.0 per 100 person- tiousness of and the susceptibility to HIV-1 could years vs. 11.6 per 100 person-years). The incidence of facilitate efforts to prevent transmission of the virus.
seroconversion was highest among the partners who To delineate the risk factors associated with het- were 15 to 19 years of age (15.3 per 100 person-years).
erosexual transmission of HIV-1 more clearly, we The incidence was 16.7 per 100 person-years among137 uncircumcised male partners, whereas there were prospectively followed couples discordant for HIV-1 no seroconversions among the 50 circumcised male status in stable sexual relationships in a group of com- partners (P<0.001). The mean serum HIV-1 RNA level munities with a high prevalence of infection with was significantly higher among HIV-1–positive sub- HIV-1 (16.1 percent), mainly subtypes A and D. We jects whose partners seroconverted than among those were able to identify these couples retrospectively whose partners did not seroconvert (90,254 copies from a community-based trial of 15,127 persons re- per milliliter vs. 38,029 copies per milliliter, P=0.01).
siding in the rural district of Rakai, Uganda.21 We There were no instances of transmission among the analyzed sociodemographic, behavioral, and biolog- 51 subjects with serum HIV-1 RNA levels of less than ic factors, with particular emphasis on the effects of 1500 copies per milliliter; there was a significant dose– serum viral load on the risk of heterosexual trans- response relation of increased transmission with in-creasing 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 2.45for seroconversion (95 percent confidence interval, Study Population
The Sexually Transmitted Diseases Control for AIDS Preven- Conclusions
tion Study, a community-based randomized trial, was conducted the risk of heterosexual transmission of HIV-1, and in Rakai between November 1994 and October 1998. The design transmission is rare among persons with levels of less and results of the study have been reported previously.21 In brief, than 1500 copies of HIV-1 RNA per milliliter. (N Engl rural communities on secondary roads were aggregated into 10 clusters; 5 clusters were randomly assigned to receive interventionfor sexually transmitted diseases, and 5 clusters were randomly as- 2000, Massachusetts Medical Society.
signed to a control group. Five community-based surveys wereconducted at intervals of 10 months.
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 ofMedicine, Makerere University, Kampala, Uganda (N.S., D.S., F.W.-M.,T.L.). Address reprint requests to Dr. Quinn at the Division of InfectiousDiseases, Johns Hopkins University, 720 Rutland Ave., Ross 1159, Balti-more, MD 21205-2196.
Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f M e d ic i ne Eligible persons were read a consent form that explained the blotting (HIV-1 Western Blot, BioMerieux-Vitek, St. Louis). Syph- study and its potential risks and benefits, and they were informed ilis was diagnosed with use of a commercial test (Toluidine Red of their rights to decline all or part of the study activities without Unheated Serum Test, New Horizons, Columbia, Md.), and pos- loss of access to clinical and educational services. The trial was ap- itive samples were confirmed by treponemal-specific tests (TPHA proved by the AIDS Research Subcommittee of the Uganda Na- Sera-Tek, Rujibero, Tokyo, Japan, or FTA-ABS IFA test system, tional Council for Science and Technology, the human-subjects Zeus Scientific, Raritan, N.J.). Urine samples were tested by a li- review boards of Columbia University and Johns Hopkins Univer- gase chain reaction for Neisseria gonorrhoeae and Chlamydia tra- sity, and the National Institutes of Health Office for Protection chomatis (LCx Probe System, Abbott Laboratories, Abbott Park, from Research Risk. Safety was assessed by an independent data Ill.) in a subgroup of subjects. Among women, self-collected vag- inal swabs were cultured for Trichomonas vaginalis (InPouch TV Subjects in both groups received identical, intensive instruction culture, BioMed Diagnostics, San Jose, Calif.) and examined mor- on the prevention of HIV-1 infection and condom use and were phologically for bacterial vaginosis with the use of Gram’s staining.
offered free condoms and voluntary, confidential serologic testing The results of measurements of serum HIV-1 RNA were not for HIV-1 and counseling by trained project counselors. Since this available during the study. Archived serum samples from the cou- was a community-based trial that enrolled all consenting adults, ples were tested in batches approximately one year after the com- the identification of couples within the general population was done pletion of the trial. Serum levels of HIV-1 RNA were quantified only retrospectively. Hence, our study differs from other investi- by a reverse-transcriptase–polymerase-chain-reaction assay (Am- gations that selectively identified and followed HIV-1–discordant plicor HIV-1 Monitor 1.5 assay, Roche Molecular Systems, Branch- couples. During our study, individual and couples counseling was burg, N.J.), as previously described.24 This assay has been shown continually offered to all subjects, who were strongly encouraged to quantitate all subtypes of HIV-1 reliably, including subtypes A to make use of this service, as recommended by the AIDS Control and D, which are present in Uganda.25 The limit of detection was Programme of the Ugandan Ministry of Health.22 All subjects were 400 copies of HIV-1 RNA per milliliter, and samples with values also strongly encouraged to obtain the results of their tests for below this limit were assigned a value of 399 per milliliter for the HIV-1 and to share the results with their partners, in accordance with the testing policy of the AIDS Control Programme.22 This Among couples in which the HIV-1–negative partner serocon- policy explicitly states that “it is the right of the patient to decide verted, the HIV-1 RNA assay was performed on the serum sam- who else to inform about the results” and thus precludes the “re- ple obtained from the HIV-1–positive index partner at the study vealing [of the] results to sexual partners or spouses.”22 The pol- visit before the 10-month interval in which there was a risk of ser- icy also specifies that “medical personnel and anybody who has, oconversion (i.e., an average of 4 to 5 months before probable ser- during the course of their work, access to confidential informa- oconversion). Couples in which there was no seroconversion were tion about the patient, does not divulge this information to third matched with couples with seroconversion according to the sex parties who are not directly involved in the care of the patient” and age (within five years) of the HIV-1–positive and HIV-1–neg- and that, “because of the stigma and discrimination arising from ative partners and the timing of the follow-up visit. For the cou- HIV infection and AIDS, it is more important that everybody ad- ples that remained discordant, we selected from the HIV-1–pos- itive partner the serum sample that was obtained closest in time Free condoms were made continuously available to the entire to that of the matched seroconverting couple. Thus, the assays were community. At each visit, health care was provided by Rakai Project frequency-matched according to sex, age, and the time at which mobile clinics, and subjects were advised to seek care in govern- samples were obtained in the case of both HIV-1–positive part- ment clinics if they had symptoms that suggested the acquisition ners who transmitted the virus and those who did not.
of sexually transmitted diseases between survey visits.
Antiretroviral drugs are not available in rural Uganda. Conse- Subjects who were legally married or in consensual union, de- quently, the HIV-1 RNA levels were not influenced by the use of fined as a culturally accepted long-term sexual relationship, were asked to provide the name and address of the spouse or consensualpartner. Such information was obtained for 75 percent of all eli- Statistical Analysis
gible couples. During the first four surveys, we were able to iden-tify 415 couples that were discordant for HIV-1 and that were Descriptive analyses were conducted separately according to age together during the interval in which there was a risk of serocon- and sex and the characteristics of the HIV-1–positive and HIV-1– version. Rates of transmission and acquisition of HIV-1 were as- negative partners. The presence or absence of sexually transmitted diseases was determined at the visit before and the one followingthe interval in which there was a risk of seroconversion, whereas Interviews and Tests
information on behavior and symptoms of sexually transmitteddisease during that interval were determined at the visit after the At base line and at each follow-up visit, subjects were interviewed interval. At each visit, subjects were asked about current symp- separately and in private by same-sex interviewers to ascertain their toms. The incidence of HIV-1 was estimated per 100 person-years sociodemographic characteristics; sexual behavior (the number of in HIV-1–negative subjects and was based on the assumption sexual partners in the past year and condom use); history of travel that seroconversion occurred at the midpoint of the 10-month outside of the district; health history, including symptoms of gen- follow-up interval. The incidence was tabulated separately accord- ital ulcer disease, genital discharge, and dysuria that were present ing to sociodemographic characteristics, behavior, and symptoms at the time of each interview and during the period between sur- and diagnoses of sexually transmitted diseases in HIV-1–positive veys; history of and treatment for sexually transmitted diseases; and partners (i.e., to indicate the risk of transmission) and in HIV-1– the presence of AIDS-defining symptoms or conditions, accord- negative partners (i.e., to indicate the risk of acquisition). ing to the World Health Organization (WHO) criteria for a pre- Tests of statistical significance included the 95 percent confi- sumptive diagnosis.23 The circumcision status of the male subjects dence intervals of the unadjusted rate ratios, two-sided P values based on chi-square tests or the chi-square test for trend, and Fish- At base line and at each follow-up visit, all subjects were asked er’s exact test.26 Formal adjustments for multiple comparisons were to provide a venous blood sample and a 10-ml first-catch urine sam- not performed for associations based on a priori hypotheses (e.g., ple, and the female subjects provided self-collected vaginal swabs; that transmission rates would increase with higher serum HIV-1 compliance was over 90 percent. Venous blood was tested for RNA loads, younger age, the absence of circumcision, and the pres- HIV-1 with two enzyme immunoassays (Vironostika HIV-1, Orga- ence of sexually transmitted diseases or their symptoms). In addi- non Teknika, Charlotte, N.C., and Cambridge Biotech, Worces- tion, we hypothesized that viral load would be higher among sub- ter, Mass.), with confirmation of discordant results by Western jects who transmitted the disease to their partners than among Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. V I R A L L OA D A N D H ET E R O S EXUA L T R A N S M I S S I O N O F H U M A N I M M U N O D E F I C I E N CY V I R U S T Y P E 1
TABLE 1. RATES OF ACQUISITION AND TRANSMISSION OF HIV-1
NO. OF CASES/
INCIDENCE/
RATE RATIO
SUBJECTS
PERSON-YR*
100 PERSON-YR
(95% CI)†
*Person-years were estimated to two decimal places and were rounded to whole numbers.
‡Chi-square for trend=0.65, P=0.45.
§Chi-square for trend=3.58, P=0.06.
those who did not. Mean and median viral loads were estimated follow-up, 22.5). The male partner was infected with on the basis of untransformed data and on data transformed to HIV-1 at base line in 228 of these 415 couples (55 the base-10 logarithm. Viral loads were analyzed for the HIV-1– percent), and the female partner was infected in 187 positive partners who transmitted the virus and for those who didnot transmit the virus, and as well as according to age and sex. The (45 percent) (Table 1). Ninety (22 percent) of the t-test was used to compare mean viral loads.26 HIV-1–negative partners seroconverted during the Multivariate adjusted rate ratios for the risk of seroconversion course of the study, for an overall incidence of 11.8 were estimated with the use of Poisson regression analysis.27 The per 100 person-years. Fifty (56 percent) of the part- viral load was the independent variable of interest and was assessedin separate models in which the actual viral load (copies per mil- ners who seroconverted were female, and 40 (44 per- liliter) was included as a categorical variable and the log-transformed cent) were male. The rate of transmission from male viral load was included as a continuous variable. For the categor- partners to female partners was not significantly dif- ical variable, a serum HIV-1 RNA level of less than 3500 copies per ferent from the rate of transmission from female part- milliliter was used as the reference category because there were no ners to male partners (12.0 per 100 person-years vs.
instances of seroconversion of HIV-1–negative subjects whose part-ners had HIV-1 RNA levels of less than 1500 copies per milliliter, 11.6 per 100 person-years). The median age at enroll- and the rate ratios of HIV-1 seroconversion were estimated for ment was 30.3 years among HIV-1–negative partners viral loads of 3500 to 9999 copies per milliliter, 10,000 to 49,999 and 29.4 years among HIV-1–positive partners (P> copies per milliliter, and 50,000 or more copies per milliliter. All 0.05). The highest incidence of seroconversion was models included terms for age (15 to 19, 20 to 29, 30 to 39, and40 to 59 years) and for the sex of HIV-1–positive partners. The among couples in the age group of 15 to 19 years number of sexual partners in the past year (one vs. two or more), (Table 1). The incidence declined with the age of both use or nonuse of condoms, circumcision or noncircumcision of the HIV-1–negative and HIV-1–positive partners, but male partner, presence or absence of symptoms of sexually trans- these trends were not statistically significant (P>0.05).
mitted diseases (genital ulcer disease, genital discharge, and dysuria),and presence or absence of sexually transmitted diseases (syphilis, Characteristics of HIV-1–Negative Partners Associated
gonorrhea, and chlamydia in both sexes and trichomonas and bac- with the Acquisition of Infection
terial vaginosis in women) were also assessed. Separate models werefitted for the characteristics of the HIV-1–positive partners and On bivariate analysis, there were no significant dif- ferences in the risk of infection among HIV-1–neg- ative partners according to the level of formal edu-cation, history of travel outside the district within the Demographic Characteristics and Incidence of HIV-1
previous year, the number of sexual partners within A total of 415 couples discordant for HIV-1 were the past year (one vs. two or more), or condom use or enrolled between the first and the fourth survey and nonuse. However, 364 of 407 HIV-1–negative part- followed for a period of up to 30 months (median ners for whom information was available (89 per- Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f M e d ic i ne TABLE 2. RATES OF ACQUISITION AND TRANSMISSION OF HIV-1, ACCORDING TO
THE CHARACTERISTICS OF THE INITIALLY HIV-1–NEGATIVE PARTNERS CHARACTERISTIC
HIV-1–NEGATIVE PARTNERS
HIV-1–POSITIVE PARTNERS
*Only subjects for whom data were available are included.
†Person-years were estimated to two decimal places and were rounded to whole numbers.
‡P<0.001 for the comparison within the group.
§P<0.05 for the comparison within the group.
cent) never used condoms (Table 2). The rate of ser- diseases (data not shown) or genital ulcer disease did oconversion among uncircumcised male subjects was not significantly increase the rate of transmission.
16.7 per 100 person-years, whereas no seroconver- However, a history of genital discharge or dysuria in sions occurred among circumcised male subjects (P< the HIV-1–positive partner was associated with a sig- 0.001). There were no significant differences in the nificantly increased transmission rate (P<0.05). The rate of acquisition of HIV-1 infection according to ei- presence of AIDS-defining symptoms or signs was ther the presence or absence of symptoms of sexually also associated with a significantly increased rate of transmitted diseases (Table 2) or the presence or ab- transmission (27.3 per 100 person-years vs. 11.4 per sence of syphilis, gonorrhea, chlamydia, trichomonas, 100 person-years, P<0.05). However, only 14 of 415 and bacterial vaginosis (data not shown).
HIV-1–positive subjects (3 percent) met the WHOcriteria for AIDS.
Characteristics of HIV-1–Positive Partners
Associated with the Transmission of Infection
HIV-1 RNA Levels and the Risk of Transmission
Transmission rates were not significantly affected Of the 415 seropositive partners, 364 (88 percent) by the level of formal education, travel history, the had detectable serum levels of HIV-1 RNA. The mean number of sexual partners within the preceding year, serum level of HIV-1 RNA among the 228 HIV-1– or condom use or nonuse. Uncircumcised male sub- positive men was 59,591 copies per milliliter (median, jects had a higher rate of transmission than circum- 15,649) and was significantly higher than the mean cised male subjects (13.2 per 100 person-years vs. 5.2 level of 36,875 copies per milliliter among the 187 per 100 person-years), but this difference was not HIV-1–positive women (median, 9655; P=0.03).
statistically significant (P=0.17). On bivariate analy- When the log-transformed values were used, the mean sis, the laboratory diagnosis of sexually transmitted (±SD) value was 4.11±0.86 log copies of HIV-1 Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. V I R A L L OA D A N D H ET E R O S EXUA L T R A N S M I S S I O N O F H U M A N I M M U N O D E F I C I E N CY V I R U S T Y P E 1
TABLE 3. MEAN AND MEDIAN VIRAL LOADS.
ALL SUBJECTS
FEMALE SUBJECTS
MALE SUBJECTS
*The P values are for the comparison with female subjects.
†P=0.001 for the comparison with HIV-1–positive subjects whose partners did not seroconvert (by Student’s t-test).
RNA among the men and 3.90±0.83 log copies of adjusted for viral load (P=0.76), and there were HIV-1 RNA among the women (P=0.008) (Table 3).
no consistent differences between male-to-female or Among couples in which the initially HIV-1–negative female-to-male transmission rates within strata of vi- partner seroconverted, the mean serum HIV-1 RNA level of the HIV-1–positive partner was significantlyhigher than that of the HIV-1–positive partner in cou- Results of Multivariate Logistic-Regression Analysis
ples in which the HIV-1–negative partner remained We constructed several Poisson regression models, seronegative (mean, 90,254 copies per milliliter vs.
the results of which are summarized in Table 4. Viral 38,029 copies per milliliter; P=0.01). When these two load was the variable most strongly predictive of the subgroups were analyzed according to sex, the log- risk of transmission. When viral load was measured transformed values were significantly higher among as a categorical variable, with HIV-1–positive partners male and female subjects whose partners serocon- with serum HIV-1 RNA levels of less than 3500 cop- verted than among male and female subjects whose ies per milliliter as the reference group, the rate ratio partners did not seroconvert (P=0.001) (Table 3).
of the risk of transmission increased from 5.80 (95 There was a significant dose–response effect with percent confidence interval, 2.26 to 17.80) for HIV-1– respect to both male-to-female transmission and positive subjects with HIV-1 RNA levels of 3500 to female-to-male transmission (P<0.001) (Fig. 1). The 9999 copies per milliliter to 11.87 (95 percent con- rate of transmission was zero among the 51 couples fidence interval, 5.02 to 34.88) for seropositive sub- in which the HIV-1–positive partner had undetect- jects with 50,000 or more copies per milliliter. When able serum levels of HIV-1 RNA or less than 1500 viral load was measured as a continuous variable, the copies per milliliter. Among HIV-1–positive partners rate ratio for the risk of transmission associated with with serum HIV-1 RNA levels of less than 3500 cop- each log increment in viral load was 2.45 (95 per- ies per milliliter, the rate of transmission was 2.2 per cent confidence interval, 1.85 to 3.26).
100 person-years, and the rates progressively increased As compared with the risk of transmission among with increasing viral loads, to a maximum of 23.0 per HIV-1–positive partners who were 15 to 19 years of 100 person-years at a level of 50,000 or more copies age, the risk of transmission decreased with older age, per milliliter. It is noteworthy that among the 90 in- after adjustment for viral load, and this decrease was stances of transmission, 5.6 percent occurred among significant for those who were 30 to 39 years of age couples in which the HIV-1–positive partner had se- (rate ratio, 0.32) and those who were 40 to 59 years rum HIV-1 RNA levels of 400 to 3499 copies per of age (rate ratio, 0.27). The interaction between age milliliter, 17.7 percent among couples in which the ser- and log-transformed viral load was not statistically opositive partner had levels of 3500 to 9999 copies significant (P=0.06). The risk of transmission was per milliliter, 40.0 percent among couples in which the lower among circumcised male subjects than among seropositive partner had levels of 10,000 to 49,999 uncircumcised male subjects, but this difference was copies per milliliter, and 36.7 percent among cou- not significant (rate ratio, 0.41; 95 percent confidence ples in which the seropositive partner had levels of 50,000 or more copies per milliliter. There was no The risk of infection increased as the HIV-1– significant difference between male-to-female and infected partner’s viral load increased and decreased female-to-male transmission rates after the results were with age among HIV-1–negative partners. The risk Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f M e d ic i ne 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 theassay was 400 HIV-1 RNA copies per milliliter. For partners with fewer than 400 HIV-1 RNA copies per milliliter, there were zerotransmissions.
of infection was zero among the 50 HIV-1–negative All participants were asked whether they wanted circumcised male subjects. A history of multiple sex- to know the results of their HIV-1 tests, all were of- ual partners, symptoms of sexually transmitted dis- fered counseling after testing and free condoms in the eases, or the laboratory diagnosis of sexually trans- privacy of their own homes, and all were told about mitted diseases had no significant effect on the risk safe-sex practices. Couples counseling was also offered to the entire community, and all subjects were strong-ly encouraged to share the results of testing with their DISCUSSION
partners. Although the rate of condom use remained Prospective studies of HIV-1–discordant couples low in the entire study population, as has been the provide important information on the efficiency of case in other studies in Uganda,28 we did observe an transmission and the biologic and behavioral vari- increase in current condom use over the four-year ables that influence the infectiousness of and suscep- study, from 4.4 percent to 7.4 percent as reported by tibility to HIV-1. Our study of heterosexual transmis- women and from 9.9 percent to 16.9 percent as re- sion among sexual partners was a community-based ported by men; these values represent some of the study in which all consenting couples, whether dis- highest rates of use in rural sub-Saharan Africa. How- cordant for HIV-1 or not, were prospectively followed ever, with this rate of condom use, HIV-1 was trans- to evaluate the risk of transmission in relation to vi- mitted to 90 of the 415 initially HIV-1–negative ral load and other characteristics. Our study sample partners, for an overall incidence of 11.8 per 100 per- is representative of the general population in this ru- son-years. This was significantly higher than the in- cidence of 1.0 per 100 person-years reported among Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. V I R A L L OA D A N D H ET E R O S EXUA L T R A N S M I S S I O N O F H U M A N I M M U N O D E F I C I E N CY V I R U S T Y P E 1
TABLE 4. ADJUSTED RATE RATIOS OF THE RISK OF TRANSMISSION
RISK OF TRANSMISSION AMONG
RISK OF ACQUISITION AMONG
COVARIATE
HIV-1–POSITIVE PARTNERS
HIV-1–NEGATIVE PARTNERS
*Each variable was adjusted for all the other variables. Poisson regression analysis was used to cal- culate the rate ratios. CI denotes confidence interval.
†These subjects served as the reference group.
‡The log (base 10) continuous model was constructed separately from the categorical estimates.
§A model was constructed that included only male subjects (228 HIV-1–positive and 187 HIV-1– ¶Estimates were based on a subgroup for which the results of a ligase chain reaction assay were available (199 HIV-1–positive subjects and 226 HIV-1–negative subjects).
¿A model was constructed that included only female subjects (187 HIV-1–positive and 228 HIV-1– couples in which both members were initially sero- missions by seropositive subjects with undetectable viral loads or with serum HIV-1 RNA levels of less The major finding of this study was the strong as- than 1500 copies per milliliter. This finding raises the sociation between increasing serum HIV-1 RNA lev- possibility that reductions in viral load brought about els and an increasing risk of heterosexual transmission by the use of antiretroviral drugs could potentially re- of HIV-1. In a finding similar to those of studies that duce the rate of transmission in this population. Such found that the risk of perinatal HIV-1 infection is as- reductions in transmission have been documented in sociated with the maternal viral load,24,29-32 we found studies of perinatal transmission,30,32,33 but not in stud- a dose–response effect: the rate of transmission in- ies of sexual transmission. Further studies measuring creased from 2.2 per 100 person-years to 23.0 per the effects of antiretroviral drugs on sexual transmis- 100 person-years as the serum HIV-1 RNA level in- creased from less than 3500 copies per milliliter to Several studies have shown a good correlation be- 50,000 or more copies per milliliter (adjusted rate ra- tween peripheral-blood viral load and viral load in tio, 11.87). In multivariate analyses, the serum HIV-1 seminal plasma34 and cervical secretions,35,36 and viral RNA level was the main predictor of the risk of trans- loads in genital secretions appear to fall in concert mission (Table 4). Each log increase in viral load was with the declines in peripheral-blood viral load after associated with an increase by a factor of 2.45 in the combination therapy.20,34,37 However, the rate of trans- risk of transmission. There were no instances of trans- mission of HIV-1 was not assessed in these studies, Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f M e d ic i ne and despite reductions in peripheral-blood and sem- and their clients in Africa have shown that the ab- inal plasma viral load, integrated viral DNA is still sence of circumcision among men increases their risk present in seminal cells, and virus can be recovered in of heterosexual acquisition of HIV-1,9,11,46 potentially vitro.38-40 However, it is apparent from our results that because of an association with an increased frequen- the rate of transmission is markedly reduced among cy of sexually transmitted diseases among uncircum- persons with very low serum viral loads.
cised men.11 This association between male circum- In multivariate analyses, we did not find a signifi- cision and a decreased risk of infection with HIV-1 cant association between the risk of HIV-1 transmis- may partially explain the low frequency of female-to- sion and the presence of sexually transmitted diseas- male transmission in U.S. studies of HIV-1–discord- es or symptoms of sexually transmitted diseases in ant couples,47 since over 70 percent of men in the HIV-1–positive partners, or between an increased sus- ceptibility to infection and sexually transmitted dis- Limitations in the interpretation of our data include eases among HIV-1–negative partners. However, gen- the fact that the interval between the measurement ital discharge and dysuria in the seropositive partner of the viral load in the index subject and documen- were significant in the unadjusted analysis. This last tation of seroconversion in the partner was 10 months, finding, even though not significant in the multivariate resulting in some imprecision as to the viral load at analysis, is compatible with findings from other stud- the time of transmission. Similarly, the diagnosis of ies in which persons with a genital discharge had in- sexually transmitted diseases was established at the creased HIV-1 RNA levels in genital secretions.41,42 visit before and the visit after the end of the interval In analyses of the risk of transmission according to in which there was a risk of seroconversion, which male or female sex, we found no significant difference may have diluted the potential association between in incidence between female-to-male transmission and sexually transmitted diseases and the risk of transmis- male-to-female transmission. The rate in each group sion of HIV-1. However, data on symptoms of sex- was about 12 per 100 person-years. For each catego- ually transmitted diseases were available for the entire ry of viral load, the rates of transmission were similar interval in which there was a risk of seroconversion, in both sexes, and these results reflect the nearly and serum viral load was a much stronger predictor equal distribution of HIV-1 infection between men of the risk of transmission than was the presence of and women in this community and in most other parts of Africa.1,43 The transmission rates reported here Heterosexual transmission involves a complex inter- reflect a combination of the probability of transmis- action between biologic and behavioral factors. Our sion per sexual act, the frequency of sexual contact, data suggest that peripheral-blood levels of HIV-1 viral shedding in the genital tract as influenced by RNA contribute dramatically to the risk of hetero- the presence of concurrent genital tract infections, sexual transmission. Serum HIV-1 RNA levels below 1500 copies per milliliter were not associated with Despite similarities in transmission rates between transmission, whereas the risk of transmission in- the sexes at each level of viral load, seropositive female creased substantially with increasing viral loads. These subjects did have significantly lower log-transformed results suggest that research is urgently needed to mean viral loads than male subjects, and this sex- develop and evaluate cost-effective methods, such as specific difference was greatest among the subjects effective and inexpensive antiretroviral therapy or vac- who transmitted the virus to their partners (mean cines, for reducing viral load in HIV-1–infected per- log-transformed viral load, 4.30 among seropositive sons. Such measures, coupled with education about female subjects and 4.62 among seropositive male safe-sex practices, condom use, HIV-1 testing and subjects; P=0.015). These data are consistent with counseling, and control of sexually transmitted dis- recent reports that female subjects have lower viral eases, could potentially reduce the infectivity of and loads than male subjects matched with them for age susceptibility to HIV-1 and prevent further sexual and CD4 count, despite the fact that they had sim- ilar rates of progression and similar decreases in theCD4 count.44,45 The mechanisms for these sex-based Supported by grants (R01 AI34826b and R01 AI34826S) from the differences in viral load are unclear.
National Institute of Allergy and Infectious Diseases; by a grant(5P30HD06826) from National Institute of Child Health and Human De- An additional finding in our study was that circum- velopment; and by the Rockefeller Foundation and the World Bank Ugan- cision was protective against HIV-1 infection, with no da Sexually Transmitted Infections Project. Some drugs and laboratory infections occurring among 50 circumcised HIV-1– tests were provided by Pfizer, Abbott Laboratories, Roche Molecular Sys-tems, and Calypte Biomedical.
negative male subjects, as compared with 40 infectionsamong 137 HIV-1–negative uncircumcised male sub- We are indebted to S. Sempala (Uganda Virus Research Institute, jects. This finding suggests that male circumcision Uganda Ministry of Health) for his support of the study; to Sharon may reduce the risk of acquisition at all HIV-1 RNA Hillier (University of Pittsburgh) for reviewing the vaginal swabsfor bacterial vaginosis; to Patricia Buist for editorial assistance; to levels. Studies among truck drivers, persons attending Richard Kline, Christopher Urban, and Denise McNairn for per- sexually transmitted disease clinics, and prostitutes forming viral-load assays; to all the study participants in Rakai Dis- Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved. V I R A L L OA D A N D H ET E R O S EXUA L T R A N S M I S S I O N O F H U M A N I M M U N O D E F I C I E N CY V I R U S T Y P E 1
trict, Uganda, for their contributions and support; and to Anthony immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Fauci, M.D., and Rodney Hoff, M.D., for their helpful suggestions 25. Michael NL, Herman SA, Kwok S, et al. Development of calibrated
viral load standards for group M subtypes of human immunodeficiency vi-
REFERENCES
rus type 1 and performance of an improved AMPLICOR HIV-1 MONI-TOR test with isolates of diverse subtypes. J Clin Microbiol 1999;37:2557- 1. UNAIDS Joint United Nations Program on HIV/AIDS. AIDS epidem-
ic update: December. Geneva: World Health Organization, 1999.
26. Armitage P. Statistical methods in medical research. Oxford, England:
2. HIV/AIDS surveillance report. Vol. 10. No. 2. Atlanta: Centers for Dis-
27. Breslow NE, Day NE. Statistical methods in cancer research. Vol. 2.
3. Vittinghoff E, Douglas J, Judson F, McKirnan D, MacQueen K, Buch-
The design and analysis of cohort studies. Lyon, France: International binder SP. Per-contact risk of human immunodeficiency virus transmission Agency for Research on Cancer, 1987. (IARC scientific publications no. between male sexual partners. Am J Epidemiol 1999;150:306-11.
4. Shiboski SC, Padian NS. Epidemiologic evidence for time variation in
28. Statistics Department, Ministry of Finance and Economic Planning
HIV infectivity. J Acquir Immune Defic Syndr Hum Retrovirol 1999;19: and Demographic Health Surveys. Uganda demographic and health survey 1995. Calverton, Md.: Macro International, 1996:48.
5. Downs AM, De Vincenzi I, European Study Group in Heterosexual
29. Mock PA, Shaffer N, Bhadrakom C, et al. Maternal viral load and tim-
Transmission of HIV. Probability of heterosexual transmission of HIV: re- ing of mother-to-child HIV transmission, Bangkok, Thailand. AIDS 1999; lationship to the number of unprotected sexual contacts. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11:388-95.
30. Mofenson LM, Lambert JS, Stiehm ER , et al. Risk factors for perina-
6. Royce RA, Seña A, Cates WJ Jr, Cohen MS. Sexual transmission of HIV.
tal transmission of human immunodeficiency virus type 1 in women treated N Engl J Med 1997;336:1072-8. [Erratum, N Engl J Med 1997;337:799.] with zidovudine. N Engl J Med 1999;341:385-93.
7. de Vincenzi I. A longitudinal study of human immunodeficiency virus
31. Mayaux MJ, Dussaix E, Isopet J, et al. Maternal virus load during
transmission by heterosexual partners. N Engl J Med 1994;331:341-6.
pregnancy and mother-to-child transmission of human immunodeficiency 8. Nelson KE, Rungruengthanakit K, Margolick J, et al. High rates of
virus type 1: the French perinatal cohort studies. J Infect Dis 1997;175: transmission of subtype E human immunodeficiency virus type 1 among heterosexual couples in northern Thailand: role of sexually transmitted dis- 32. Shaffer N, Chuachoowong R , Mock PA, et al. Short-course zidovu-
eases and immune compromise. J Infect Dis 1999;180:337-43 [Erratum, dine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999;353:773-80.
9. Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of
33. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zi-
health benefits and risks. Sex Transm Infect 1998;74:368-73.
dovudine treatment, and the risk of transmission of human immunodefi- 10. Halperin DT, Bailey RC. Male circumcision and HIV infection: 10
ciency virus type 1 from mother to infant. N Engl J Med 1996;335:1621-9.
years and counting. Lancet 1999;354:1813-5.
34. Gupta P, Mellors J, Kingsley L, et al. High viral load in semen of hu-
11. Cameron DW, Simonsen JN, D’Costa LJ, et al. Female to male trans-
man immunodeficiency virus type 1-infected men at all stages of disease mission of human immunodeficiency virus type 1: risk factors for serocon- and its reduction by therapy with protease and nonnucleoside reverse version in men. Lancet 1989;2:403-7.
transcriptase inhibitors. J Virol 1997;71:6271-5.
12. Fleming DT, Wasserheit JN. From epidemiological synergy to public
35. Hart CE, Lennox JL, Pratt-Palmore M, et al. Correlation of human
health policy and practice: the contribution of other sexually transmitted immunodeficiency virus type 1 RNA levels in blood and the female genital diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; 36. Iversen AK, Larsen AR , Jensen T, et al. Distinct determinants of hu-
13. Cohen MS. Sexually transmitted diseases enhance HIV transmission:
man immunodeficiency virus type 1 RNA and DNA loads in vaginal and no longer a hypothesis. Lancet 1998;351:Suppl III:sIII5-sIII7.
cervical secretions. J Infect Dis 1998;177:1214-20.
14. Lee TH, Sakahara N, Fiebig E, Busch MP, O’Brien TR , Herman SA.
37. Vernazza PL, Gilliam BL, Dyer J, et al. Quantification of HIV in se-
Correlation of HIV-1 RNA levels in plasma and heterosexual transmission men: correlation with antiviral treatment and immune status. AIDS 1997; of HIV-1 from infected transfusion recipients. J Acquir Immune Defic 38. Haase AT, Schacker TW. Potential for the transmission of HIV-1 de-
15. Ragni MV, Faruki H, Kingsley LA. Heterosexual HIV-1 transmission
spite highly active antiretroviral therapy. N Engl J Med 1998;339:1846-8.
and viral load in hemophilic patients. J Acquir Immune Defic Syndr Hum 39. Zhang H, Dornadula G, Beumont M, et al. Human immunodeficien-
cy virus type 1 in the semen of men receiving highly active antiretroviral 16. Operskalski EA, Stram DO, Busch MP, et al. Role of viral load in het-
therapy. N Engl J Med 1998;339:1803-9.
erosexual transmission of human immunodeficiency virus type 1 by blood 40. Coombs RW, Speck CE, Hughes JP, et al. Association between cultur-
transfusion recipients. Am J Epidemiol 1997;146:655-61.
able human immunodeficiency virus type 1 (HIV-1) in semen and HIV-1 17. Pedraza MA, del Romero J, Roldan F, et al. Heterosexual transmission
RNA levels in semen and blood: evidence for compartmentalization of of HIV-1 is associated with high plasma viral load levels and a positive viral HIV-1 between semen and blood. J Infect Dis 1998;177:320-30.
isolation in the infected partner. J Acquir Immune Defic Syndr Hum Ret- 41. Fiscus SA, Vernazza PL, Gilliam B, Dyer J, Eron JJ, Cohen MS. Fac-
tors associated with changes in HIV shedding in semen. AIDS Res Hum 18. Moore JP. Coreceptors: implications for HIV pathogenesis and thera-
Retroviruses 1998;14:Suppl 1:S27-S31.
42. Cohen MS, Hoffman IF, Royce RA, et al. Reduction of concentration
19. Hoffman TL, MacGregor RR , Burger H, Mick R , Doms RW, Coll-
of HIV-1 in semen after treatment of urethritis: implications for prevention man RG. CCR5 genotypes in sexually active couples discordant for human of sexual transmission of HIV-1. Lancet 1997;349:1868-73.
immunodeficiency virus type 1 infection status. J Infect Dis 1997;176: 43. Quinn TC. Global burden of the HIV pandemic. Lancet 1996;348:
20. Musicco M, Lazzarin A, Nicolosi A, et al. Antiretroviral treatment of
44. Farzadegan H, Hoover DR , Astemborski J, et al. Sex differences in
men infected with human immunodeficiency virus type 1 reduces the inci- HIV-1 viral load and progression to AIDS. Lancet 1998;352:1510-4.
dence of heterosexual transmission. Arch Intern Med 1994;154:1971-6.
45. Sterling TR , Lyles CM, Vlahov D, Astemborski J, Margolick JB,
21. Wawer MJ, Sewankambo NK, Serwadda D, et al. Control of sexually
Quinn TC. Sex differences in longitudinal human immunodeficiency virus transmitted diseases for AIDS prevention in Uganda: a randomised com- type 1 RNA levels among seroconverters. J Infect Dis 1999;180:666-72.
munity trial. Lancet 1999;353:525-35.
46. Lavreys I, Rakwar JP, Thompson ML, et al. Effect of circumcision on
22. AIDS Control Programme. HIV testing policy. Entebbe, Uganda:
incidence of human immunodeficiency virus type 1 and other sexually Ministry of Health, Health Education Printing Press, October 1992:1-8.
transmitted diseases: a prospective cohort study of trucking company em- 23. Acquired immune deficiency syndrome (AIDS): workshop on AIDS in
ployees in Kenya. J Infect Dis 1999;180:330-6.
central Africa, Bangui, 22-25 October 1985. In: Weekly epidemiological 47. Padian NS, Shiboski SC, Glass SO, Vittinghoff E. Heterosexual trans-
record. Vol. 60. No. 44. Geneva: World Health Organization, 1985:342.
mission of human immunodeficiency virus (HIV) in northern California: 24. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human
results from a ten-year study. Am J Epidemiol 1997;146:350-7.
Downloaded from nejm.org at CILEA BIBLIOSAN on May 14, 2011. For personal use only. No other uses without permission. Copyright 2000 Massachusetts Medical Society. All rights reserved.

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