HIV Transmission by Stage of Infection
• JID 2005:191 (1 May) • 1403
M A J O R A R T I C L E
Rates of HIV-1 Transmission per Coital Act,
by Stage of HIV-1 Infection, in Rakai, Uganda
Maria J. Wawer,1Ronald H. Gray,2Nelson K. Sewankambo,5David Serwadda,6Xianbin Li,2Oliver Laeyendecker,3
Noah Kiwanuka,7Godfrey Kigozi,7Mohammed Kiddugavu,7Thomas Lutalo,7Fred Nalugoda,7Fred Wabwire-Mangen,6
Mary P. Meehan,1and Thomas C. Quinn3,4
1Heilbrun Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York;
of Population and Family Health Sciences, Johns Hopkins Bloomberg School of Public Health,
Institutions, Baltimore, and
of Medicine and Clinical Epidemiology Unit and
Uganda Virus Research Institute, Entebbe
3Department of Medicine, Johns Hopkins Medical
4National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
6Institute of Public Health, Makerere University, Kampala, and
8Rakai Health Sciences Program,
(See the editorial commentary by Cohen and Pilcher, on pages 1391–3.)
We estimated rates of human immunodeficiency virus (HIV)–1 transmission per coital act in
HIV-discordant couples by stage of infection in the index partner.
We retrospectively identified 235 monogamous, HIV-discordant couples in a Ugandan population-
based cohort. HIV transmission within pairs was confirmed by sequence analysis. Rates of transmission per coital
act were estimated by the index partner’s stage of infection (recent seroconversion or prevalent or late-stage in-
fection). The adjusted rate ratio of transmission per coital act was estimated by multivariate Poisson regression.
The average rate of HIV transmission was 0.0082/coital act (95% confidence interval [CI], 0.0039–
0.0150) within ∼2.5 months after seroconversion of the index partner; 0.0015/coital act within 6–15 months after
seroconversion of the index partner (95% CI, 0.0002–0.0055); 0.0007/coital act (95% CI, 0.0005–0.0010) among
HIV-prevalent index partners; and 0.0028/coital act (95% CI, 0.0015–0.0041) 6–25 months before the death of
the index partner. In adjusted models, early- and late-stage infection, higher HIV load, genital ulcer disease, and
younger age of the index partner were significantly associated with higher rates of transmission.
The rate of HIV transmission per coital act was highest during early-stage infection. This has
implications for HIV prevention and for projecting the effects of antiretroviral treatment on HIV transmission.
Model estimates suggest that the rate of heterosexual
HIV-1 transmission per coital act follows a U-shaped
curve, being highest during the postseroconversion pe-
riod, lower during latency, and increasing with ad-
vancing disease [1–4]. This is supported by findings
that blood HIV load, which is higher during the post-
seroconversion period and during advanced disease, is
the principal predictor of heterosexualtransmission[5–
Received 3 August 2004; accepted 8 November 2004; electronically published
30 March 2005.
Reprints or correspondence: Dr. Maria J. Wawer, Heilbrun Dept. of Population
and Family Health, Mailman School of Public Health, Columbia University, 60
Haven Ave., Floor B-2, New York, NY 10032 (firstname.lastname@example.org).
Presented in part: 10th Conference on Retroviruses and OpportunisticInfections,
Boston, 10–14 February 2003 (abstract 40).
Financial support: National Institute of Allergy and Infectious Diseases (grant
R01 AI34826); National Institute of Child Health and Development (grant
5P30HDS06826); Fogarty Foundation (grant 5D43W00010); US National Institutes
of Health; World Bank Uganda STI Project.
The Journal of Infectious Diseases
? 2005 by the Infectious Diseases Society of America. All rights reserved.
8]. However, empirical data on heterosexual HIV in-
fectivity by stage of disease are limited. We report the
rate of HIV transmission per coital act in 235 hetero-
sexual, HIV-discordant couples, with one HIV-infected
partner and one monogamous HIV-uninfectedpartner,
who were identified retrospectively from a population-
based cohort in Rakai, Uganda.
SUBJECTS AND METHODS
Between 1994 and 1999, we enrolled 15,127 adults into
a community randomized trial of STD Control forAIDS
Prevention, in Rakai District, Uganda. Study methods,
described elsewhere [9, 10], are summarized briefly.
All consenting residents 15–59 years old, who lived
in 56 rural villages, were surveyed in the home at 10-
month intervals for up to 40 months. Trial participants
were enrolled as individuals; provided written, informed
consent; and were guaranteedconfidentiality.Condoms
and voluntary HIV counseling and testing, for individ-
uals and for couples, were promoted and provided free
1404 • JID 2005:191 (1 May) • Wawer et al.
of charge. Participants were encouraged to share their HIV
results with their partners; however, Uganda MinistryofHealth
policy does not allow the involuntary disclosure of HIV results
to third parties, including partners.Datalinkagetoidentify
couples was conducted after completion of the trial. Antiret-
roviral therapy (ART) was not available in Uganda at the time
of the study, but participants were offered free general health
care and treatment for opportunistic infections. The study was
approved by human subjects review boards at the UgandaVirus
Research Institute, the AIDS Research Subcommittee of the
Ugandan National Council for Science and Technology, Co-
lumbia University, and Johns Hopkins University.
At each 10-month survey visit, participants provided sero-
logical samples and were administered a sociodemographic,be-
havioral, and health interview, which included questions on
numbers of partners and the respondent’s relationship to each
partner. Coital frequency was determined by asking, “When
you have relationships with this partner, how frequentlydoyou
usually have intercourse per day, per week and per month?”
The monthly frequency of intercourse was used to estimate the
number of coital acts during the period of observation. Male
and female partners reported similar coital frequency. In cou-
ples in which the woman was the HIV-infected index partner,
women reported a mean of 9.7 acts/month, and men reported
a mean of 9.8 coital acts/month. In couples in which the man
was the HIV-infected index partner, women reported a mean
of 8.8 coital acts/month, and men reported a mean of 8.3 coital
Serum, urine, and self-administered vaginal swab samples
were collected from all participants at each 10-month survey
visit. Serological testing was conducted for syphilis (Toluidine
Red Unheated Serum Test [New Horizons], with confirmatory
Treponema pallidum hemagglutination assay [Sera-Tek; Ruji-
bero]) and for herpes simplex virus type 2 (HSV-2; HerpeSelect
2 ELISA IgG [Focus], with Western blot confirmation  of
ELISA-positive samples). Urine samples were assayed for Neis-
seria gonorrhoeae and Chlamydia trachomatis (ligase chain re-
action on urine samples [LCx Probe System; Abbott Labora-
tories]). In women, vaginal swabs were tested for Trichomonas
vaginalis (InPouch TV culture; BioMed Diagnostics) and bac-
terial vaginosis (quantitativemorphologyofgram-stainedslides).
HIV serostatus was determined by use of 2 EIAs (Vironostika
HIV-1; Organon Teknika and Cambridge Biotech). EIA-discor-
dant samples and new HIV seroconversions were confirmed by
Western blot (HIV-1 Western Blot; Bio-Merieux-Vitek). The se-
rum HIV load in HIV-positive partners was determinedbyRNA
reverse-transcription polymerase chain reaction (AmplicorHIV-
1 Monitor 1.5 Assay; Roche Molecular Systems). HIV load was
determined in the first serum sample available after HIV sero-
conversion (the incident index group), the first serum sample
and the last serum sample available (the late-stage index group).
however, in the present analysis, too few incident and late-stage
index partners had A or A/D infections to allow an assessment
of the effects of subtype by stage of infection.
After completion of the trial, analyses identified 414 HIV-
discordant couples who subsequently received at least 1 follow-
up visit that permitted the retrospective assessment of HIV
transmission. In 239 of these couples, the HIV-uninfectedpart-
ners reported that they were monogamous (defined as having
only 1 sex partner during the period of observation). In 72 of
239 couples, the HIV-negative partner acquired HIV during
follow-up. At the time of the retrospective analysis reported
here, archival serum samples were available from both partners
in 46 (64%) of 72 couples with seroconversion, which per-
mitted the assessment of molecular linkage between the index
partner’s and the seroconverting partner’s HIV-1 strains. Viral
sequence data from the gag and gp41 regions  were com-
pared in both partners on the basis of sequence distance and
phylogenetic inferences, by use of bootstrap methods [8, 14–
16]. Four (8.7%) of 46 couples had nonhomologous virus and
were excluded from this analysis: 3 of these 4 couples were
originally in the prevalent index group, and 1 was in the late-
stage index group. In the remaining 26 couples in whom the
HIV-uninfected partner seroconverted, there was insufficient
remaining archival serum samples from 1 or both partners to
assess molecular linkage. The behavioralandsociodemographic
characteristics of the 26 couples and the HIV load distribution
of the HIV-infected index partners were similar to those of the
46 couples in whom we examined molecular linkage. Wewould
expect their rate of nonmarital HIV acquisition to be similar
to the modest level observed in the couples with molecular
assessment, resulting in ∼2 misclassifications. We thus included
these 26 couples in the present analysis, for a total of 235
couples for whom we present results.
In 23 couples, both partners were HIV uninfected at enroll-
ment, and the index partner seroconverted during follow-up
(incident index couples). In 161 couples, the index partner was
HIV infected at enrollment andsurvivedduringfollow-up(prev-
alent index couples), and, in 51 couples, the index partner was
HIV infected at study entry and died during follow-up (late-
reported homosexual contact, anal intercourse, blood transfu-
sion, or injection drug use during the period of observation.
For the 23 couples who entered as concordant HIV negative,
and the partner who reported extramarital sexual contact was
assumed to be the HIV-infectedindexpartner.Inthe161couples
with a HIV-infected prevalent index partner, the mean follow-
up time was 30.6 months. In the 51 couples in which the HIV-
HIV Transmission by Stage of Infection • JID 2005:191 (1 May) • 1405
infected index partner died, the mean follow-up time was 26.9
months. Death was estimated to have occurred at the midpoint
of the intersurvey period, ∼5 months after the preceding inter-
view, and HIV transmission was assessed for each of the 10-
month intervals before the last data collection (i.e., 6–15 and16–
to assess transmission during the months immediately preced-
ing death, because more than one-half of the surviving spouses
moved away from the area shortly after their partner’s death,
before the next scheduled 10-month follow-up survey visit. Of
the 13 spouses who were HIV uninfected at the time of the last
interview before the partner’s death and who remained in the
community, none had seroconverted.
In the incident index couples, the index partner’s infection
was assumed to have occurred at the midpoint of the inter-
survey period, ∼5 months after the previous survey visit. In
the 10 couples in which both partners seroconverted during
the same follow-up interval, transmission from the index part-
ner to the initially uninfected partner was estimated to have
occurred ∼2.5 months after the seroconversion of the index
partner—that is, at the midpoint of the estimated 5-month pe-
riod during which the uninfected partner was exposed to HIV
by the newly infected index partner. In the prevalent and late-
stage index groups, transmissiontotheinitiallyuninfectedpart-
ner was estimated to have occurred at the midpoint of a given
The average rate of HIV transmission per coital act for each
exposure interval was estimated as the number of seroconver-
sions divided by the total number of coital acts during an
exposure interval. Rates of transmission per coital act were
examined by use of the HIV-infected index partner’s sociode-
mographic, behavioral, andhealthcovariates.Symptomsofsex-
ually transmitted infections (STIs)—including genitalulcerdis-
ease (GUD), discharge or dysuria, and symptoms potentially
related to HIV/AIDS—were ascertained via interview; the pres-
ence of clinical signs was assessed by physical examination. For
characteristics that changed over time (e.g., GUD or potential
AIDS-related symptoms and condom use), time varying status,
as reported for each follow-up period, was used in analyses.
Adjusted rate ratios (RRs) of transmission per coital act and
95% confidence intervals (95% CIs) were estimated by Poisson
multiple regression by use of the natural logarithm of the total
number of coital acts as an offset term. Robust SEs were es-
timated by generalized estimating equation methods, to adjust
for correlated data. Covariates included in the Poisson model
were those variables that were found to be significantly associ-
ated with transmission per coital act in univariate analyses.
Because of the strong correlation between HIV load and prob-
ability of transmission, separate models were constructed with
and without the HIV load covariate.
The mean coital frequency was 10.2 coital acts/month(median,
8.3 coital acts/month) among couples with an incident index
partner and 10.0 coital acts/month (median, 8.3 coital acts/
month) among couples with a prevalent index partner. Coital
frequency decreased before the death of an index partner, from
a mean of 8.7 coital acts/month (median, 8.0coitalacts/month)
during the 16–25 months before death to a mean of 6.2 coital
acts/month (median, 5.2 coital acts/month) during the 6–15
months before death.
Approximately 5 months after seroconversion of an index
partner, the median serum HIV load was 30,000 copies/mL
(log10HIV load, 4.48 copies/L; range, ?399 [undetectable]–
3,100,000 copies/mL); by 15 months, the median HIV load had
decreased to 2600 copies/mL. Among prevalent index partners,
the median serum HIV load increased from 10,300 copies/mL
(log10HIV load, 4.01 copies/mL) at study entry to 15,000copies
(log10HIV load, 4.18 copies/mL) after 30 months of follow-
up. Among late-stage index partners, the median HIV load was
112,600 copies/mL (log10HIV load, 5.05 copies/mL) at the date
of the last test, which was conducted, on average, 5 months
who transmitted infection to their partners and the rate of
transmission per coital act, by stage of HIV infection and by
interval of follow-up. A total of 68 (28.9%) of 235 index part-
ners transmitted HIV to their initially uninfected partners.The
proportion of HIV-positive partners transmitting infectionwas
highest among incident index partners, of whom 10 (43.4%)
of 23 transmitted infection within ∼2.5 months and 13 (56.5%)
of 23 transmitted infection within ∼35 months after their own
seroconversion. Prevalent index partners transmitted infection
at an average annual rate of 8.4% (range, 6.7%–10.9%).Among
during the ∼6–35 months before death.
The overall rate of HIVtransmissionpercoitalactwas0.0012
(95% CI, 0.0009–0.0015). Transmission per act was highest in
the interval immediately after the acquisition of HIV by the
index partner (0.0082/coital act [95% CI, 0.0039–0.0150]), un-
der the assumption of ∼2.5 months of exposure for the HIV-
negative partner (table 1 and figure 1). During the subsequent
10-month interval (∼6–15 months after seroconversion by the
index partner), the rate of transmission decreased to 0.0015/
coital act (95% CI, 0.0002–0.0055), which was not significantly
different from that observed among partners of prevalentindex
partners (0.0007/coital act [95% CI, 0.0006–0.0011]). Among
late-stage index partners, the rate of transmission per coital act
increased significantly during the last 2 follow-up intervals be-
fore death (6–25 months before death, 0.0036/coital act [95%
By univariate analyses (not shown), characteristics of index
1406 • JID 2005:191 (1 May) • Wawer et al.
and by interval of follow-up, Rakai, Uganda, 1994–1999.
The proportion of HIV transmissions and HIV transmission rates per coital act by, stage of infection
no. of index partners (%)Coital acts, no.
Rate of transmission
per coital act (95% CI)
Incident index partner
Time after index seroconversion, months
All incident index partners combined
Prevalent index partner
Follow-up interval, months
All prevalent index partners combined
Late-stage index partner
Time before index partner’s death, months
All late-stage index partners combined
All couples combined
aBased on ∼2.5 months of partner exposure after the initial infection in the HIV-positive index partner.
bTwo 10-month intervals were combined because of small numbers.
CI, confidence interval.
partners that were associated with a higher rate of HIV trans-
mission per coital act were younger age (15–29 years), higher
HIV load (?3.50 log10copies/mL), and the presence of GUD.
No significant association was seen with the sex of the index
partner, circumcision status (in male index partners), AIDS-
defining symptoms, symptoms of discharge or dysuria, or lab-
oratory evidence of STIs. Forty-seven couples (19.6%)reported
the occasional use of condoms, and no couple reported con-
sistent use. There was no significant difference in the rate of
HIV transmission per coital act with inconsistent condom use,
compared with no reported use, at any stage of infection.
Table 2 shows unadjusted and adjusted RRs of HIV trans-
mission per coital act by stage of HIV infection and by char-
acteristics of index partners that were significant according to
univariate analysis. In the adjusted model that included HIV
load, younger age (!30 years; RR, 2.38), the presence of GUD
(RR, 2.04), increasing quartiles of HIV load (RR, 7.06 for the
highest quartile), and early- and late-stage HIV infection (RR,
4.98 and 3.49, respectively) remained significantly associated
with a higher risk of transmission per coital act. The exclusion
of HIV load from the model resulted in higher RRs for trans-
mission risk during early-stage (RR, 7.23) and late-stage (RR,
The overall rate of HIV transmission observed in these dis-
cordant couples, 0.0012/coital act, is consistent with previous
estimates from Rakai , Europe, and North America [3, 17].
The present analysis, however, provides the first empirical data
on the substantial variation in transmission by stage of HIV-1
infection. After seroconversion of the index partner, the rate
of transmission (0.0082/coital act) within the first 2.5 months
was almost 12-fold higher than that observed inprevalentindex
couples (0.0007/coital act). The rate then increasedsignificantly
again ∼2 years before the index partner’s death (table 1 and
figure 1). Risks of transmission per act remained significant-
ly higher during early- and late-stage HIV infection, after ad-
justment for multiple covariates (table 2); this pattern is con-
sistent with model estimates [1, 18, 19].
In the 46 couples with one seroconverting partner for whom
we conducted molecular linkage, 191% of the seroconverting
partners acquired a virus strain that was homologous to that
found in the infected index partner: the 4 couples with non-
homologous virus strains were excluded from the analysis.None
of the partners reported anal intercourse during follow-up,
consistent with the fact that we observe virtually no evidence
of anal or rectal trauma compatible with anal intercourse in
HIV Transmission by Stage of Infection • JID 2005:191 (1 May) • 1407
HIV transmission per coital act, and 95% confidence intervals, by follow-up interval
Table 2. Unadjusted and Poisson-adjusted rate ratios (RRs) of HIV transmission per coital act, Rakai, Uganda, 1994–1999.
Characteristic of HIV-positive
No. of index partners
(or index partner
Unadjusted RR of HIV
transmission (95% CI)
Adjusted RR of HIV
transmission (95% CI)
model with HIV load
Adjusted RR of HIV
transmission (95% CI)
model without HIV load
HIV load, quartile, log10
Stage of HIV infection
3.49 (1.76–6.92 )
aDenominator denotes no. of intervals in which GUD was present or absent.
bBased on the first 5 months after the index partner’s seroconversion.
cBased on the 6–25 months before the index partner’s death.
dBased on all available follow-up intervals (i.e., up to 40 months).
CI, confidence interval; GUD, genital ulcer disease.
Rakai Program STD clinics. In addition, reported receipt of
injections is not associated with the acquisition of HIV in this
population . The data thus reflect the effects of stage of
HIV infection on heterosexual vaginal transmission.
We retained the 26 couples with proven transmission for
whom we could not conduct molecular linkage (because of
insufficient archival serum samples) in the analysis. Their char-
acteristics did not differ from those of the 46 couples for whom
linkage analysis was possible and for whom we observed a low
rate (8.7%) of nonmarital HIV acquisition. It is thus possible
that ∼2 of 26 couples also acquired HIV from outside the
marital union, but this degree of misclassification would have
only a minimal effect on study results.
The 40-month maximum follow-up period in our analysis
did not permit observation of any couples for the entire period
between seroconversion of the index partner and death—a pe-
riod of 8–10 years, on average, in rural Uganda [21, 22]. How-
ever, we were able to reconstruct the probable pattern of trans-
mission rates during the course of infection. In 23 couples, the
index partner seroconverted within a known 10-month period.
Although the timing of index infection was not known in the
161 couples with a prevalent index partner, most of them were
1408 • JID 2005:191 (1 May) • Wawer et al.
monitored for at least 3 10-month intervals, and the rate of
transmission was relatively stable over time, providing an es-
timate of the average transmission rate per act during latent
HIV infection. A total of 51 index partners died; the rate of
HIV transmission per coital act ?2 years before death was not
significantly different from that observed during latency or ?6
months after seroconversion of the index partner (table 1 and
figure 1), which suggests overlap among the 3 groups.
We were unable to observe the magnitude or the duration
of the peak viremia or the rate of HIV transmission per coital
act during the weeks immediately after HIV acquisition in the
index partner. Although the median serum HIV load observed
∼5 months after seroconversion(30,000copies/mL)wassimilar
to levels observed in other populations at a comparable time
point , recent data from Malawi have suggested a peak HIV
load of 6.10 log10copies/mL (11 millionRNAcopies/mL)shortly
after the acquisition of HIV . The rate of transmission per
coital act may thus be very high for a short period immediately
after HIV infection. In Rakai couples, if the average length of
exposure between infection of the index partnerandHIVtrans-
mission was only 1 month (encompassing∼10coitalacts),rather
than the 2.5 months that we estimated, the rate of transmission
during this period could be as high as 0.02/coital act. In pop-
ulations, the epidemiological effects of different magnitudes
and durations of the peak rate of transmission would depend
on the numbers of partners, coital frequency, and the structure
of sexual networks [1, 25–27].
Because we could not observe the effect of short-term varia-
tions in HIV load on transmission, this may underestimate the
suggests, however, that HIV load may not explain all of the
increased risk seen during early-stage disease. Potential contrib-
uninfected partners and the presence of GUD. In Rakai, we
observed high rates of genital ulcers, particularly among HSV-
2–seropositive persons, during early-stage HIV infection .
The likelihood of transmission within a partnership over time
is likely to be heterogeneous and nonlinear . Our data do
not capture the effects of short-term variations in infectivityand
act during different stages of HIV infection in the index partner.
In couples with prevalent index partners,therateoftransmission
per coital act remained relatively constant duringeach10-month
period of the 40-month follow-up, which suggests that the av-
erage infectivity rate per coital act was stable during this period.
Of all the 741 Rakai couples with HIV infection who were
retrospectively identified between 1994 and 1999, 414 (55.9%)
were HIV discordant and 327 (44.1%) were concordant HIV
positive at enrollment. In the present study, only 13 (57%) of
23 of initiallynegativepartnersremaineduninfected∼5months
after the index partner seroconverted. Couples in whom trans-
mission did not occur during early infection, and those who
remained persistently discordant over time, may represent a
selected subgroup of “survivors” in whom either the index
partners were less infectious and/or the seronegative partners
to examine such potential factors.
The Rakai data were collected from stable heterosexual cou-
ples, whose primary risk was through vaginal intercourse, and
additional studies are required to examine transmission by stage
of HIV infection in other epidemic settings. Nonetheless, our
data have a number of clinical and epidemiologicalimplications.
The highest rate of transmission per coital act, as well as the
highest proportion of transmissions, occurred during early-
stage infection in index partners, a time when few serocon-
verters know their HIV status or receive ART. Although the
rate was also higher during late-stage infection, the overallcon-
tribution of the latter to a heterosexual HIV epidemic is likely
to be limited, because individuals with advanced HIV infection
report less sexual intercourse and have fewer partners, andonly
a minority of couples remain discordant by this stage. Thus,
ART, initiated relatively late during infection, under current
guidelines , may have only a modest impact on HIV trans-
mission . Also, because most HIV transmissions occur be-
fore index cases are eligible to receive ART, the heterosexual
spread of drug-resistant HIV may be modest inthispopulation.
Measures that prevent primary HIV infection or reduce early
viremia (as may occur with HIV vaccines) are likely to have a
greater effect than ART on the spread of HIV. Increased efforts
to identify persons with early-stage HIV infection are also war-
ranted, to promote safe behaviors, and, where appropriate, to
provide ART [19, 30]. In conclusion, the empirical estimates
of the rates of heterosexual HIV transmission per coital act, by
stage of HIV infection in index partners, reported here show
high rates of transmission during early- and late-stage disease,
which may assist in epidemic modeling, in the design and eval-
uation of HIV prevention strategies, and in the assessment of
the likely epidemiologic impact of ART.
We thank Dr. S. Ssempala (Director [Retired], Uganda Virus Research
Institute), for his continued support during the study; and Drs. R. Lal and
C. Yang (Centers for Disease Control and Prevention), for their assistance
in the genetic linkage of the transmission pairs.
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