Early Human Immunodeficiency Virus (HIV) Infection in the HIV

23
Early Human Immunodeficiency Virus (HIV) Infection in the HIV Network
for Prevention Trials Vaccine Preparedness Cohort: Risk Behaviors, Symptoms,
and Early Plasma and Genital Tract Virus Load
Connie L. Celum,1 Susan P. Buchbinder,3
Deborah Donnell,2 John M. Douglas, Jr.,6
Kenneth Mayer,7 Beryl Koblin,9 Michael Marmor,10
Sam Bozeman,8 Robert M. Grant,4 Jorge Flores,11
and H. W. Sheppard5
1
University of Washington and 2Fred Hutchinson Cancer Research
Center, Seattle; 3San Francisco Department of Public Health
and 4Gladstone Institute of Virology and Immunology, University
of California, San Francisco, and 5Viral and Rickettsial Disease
Laboratory, California Department of Health Services, Berkeley;
6
Denver Department of Public Health, Denver, Colorado; 7Memorial
and Miriam Hospitals, Brown University and Fenway Community
Health Center, Boston, and 8Abt Associates, Cambridge,
Massachusetts; 9New York Blood Center and 10New York University
School of Medicine, New York; 11Division of AIDS, National Institute
of Allergy and Infectious Diseases, Bethesda, Maryland
Risk behaviors, symptoms, and virologic characteristics were studied among 103 human
immunodeficiency virus (HIV) seroconverters in vaccine preparedness cohorts during
1995–1998. Overall, 83% of subjects were men who had sex with men; most reported multiple
risk episodes and symptoms (84%, >1 symptom) during seroconversion. Acute HIV was
diagnosed in only 8 of 50 who sought medical care. Median initial pretreatment plasma virus
load was 25,800 copies/mL (range, undetectable–262,000 copies/mL) a mean of 4 months after
seroconversion, and 9.7% had nucleoside-associated mutations; none had multidrug resistance.
Semen virus load was more variable, 1.3 log10 lower and modestly correlated (r p .28; 95%
confidence interval, 0.16–0.42) with plasma among untreated men. When the plasma RNA
level was !5000 copies/mL, 32% of untreated men, 13% on nucleoside regimens, and 7% on
protease inhibitor–containing regimens had detectable seminal RNA. Acute HIV was seldom
diagnosed, representing missed opportunities for early treatment and prevention. Most subjects had several relatively stable virus loads before initiation of antiretrovirals, indicating
feasibility of assessing HIV vaccines on virus set point in efficacy trials.
Studies of early human immunodeficiency virus (HIV) type 1
infection have focused on pathogenesis, early therapy, acquisition
of antiretroviral resistant virus, and the role of primary infection
in propagation of the epidemic. However, much published research stems from referral-based cohorts of largely symptomatic
seroconverters and thus may not be representative of asymptomatic or mildly symptomatic seroconverters. Contemporary cohorts of seroconverters provide relevant data for HIV vaccine
efficacy trials; pretreatment quantification of virus load among
HIV vaccine recipients who become infected may be important
to assess the effect of HIV vaccines on virus set point and kinetics
for vaccines that do not achieve sterilizing immunity [1, 2]. The
Received 17 July 2000; revised 15 September 2000; electronically published
8 December 2000.
Presented in part: XII World AIDS Conference, Geneva, 28 June–3 July
1998 (presentation 164).
Written informed consent was obtained from all study participants, in
accordance with human subjects guidelines of each institution.
Reprints or correspondence: Dr. Connie Celum, University of Washington
HIV Prevention Trials Unit, Harborview Medical Center, Box 359927, 325
9th Ave., Seattle, WA 98104 ([email protected]).
The Journal of Infectious Diseases 2001; 183:23–35
q 2001 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2001/18301-0004$02.00
measurement of clinical progression among vaccine breakthrough infections is hampered by the length of follow-up required and the effect of antiviral treatment recommended for
primary HIV infection. Given the effect of highly active antiretroviral therapy (HAART) on plasma virus load (PVL), as well
as clinical progression, it is important to assess the feasibility of
obtaining pretreatment virus loads for the assessment of HIV
vaccines on virus set point and disease progression.
Epidemiologists and mathematical modelers have hypothesized that acute HIV infection may fuel the HIV epidemic for
both behavioral and biologic reasons [3–5]. In the first few
The content of this publication does not necessarily reflect the views or
policies of the US Department of Health and Human Services nor does
mention of trade names, commercial products, or organizations imply endorsement by the US government.
Financial support: HIV Network for Prevention Trials (HIVNET) National Institutes of Health (NIH) contracts AI-35176 (Abt Associates), AI45200 (Fred Hutchinson Cancer Research Center), and AI-45202 (Central
Laboratory) and subcontracts with Denver Department of Public Health,
Fenway Community Health Center, Howard Brown Health Center, New
York Blood Center, San Francisco Department of Public Health, and University of Washington. At New York University School of Medicine, additional support was provided by General Clinical Research Center grant
RR-00096 (National Center for Research Resources, NIH) and Center for
AIDS Research grant AI-27742.
24
Celum et al.
weeks after infection, PVL can be 1106 copies/mL [6, 7], and
this may be a period of increased infectivity, given the recently
described relationship between serum virus load and HIV transmission [8]. However, there are limited data on the relationship
between virus load in blood and genital secretions during early
infection [9–12], and it is possible that the relationship between
blood or genital tract virus load and transmission is different
in acute than in late infection. In addition, although some sexually transmitted diseases (STDs), such as gonococcal urethritis
[13] and genital herpes [14], are associated with increased genital
HIV shedding in chronic HIV infection, the prevalence of STDs
and their effect on genital HIV shedding and transmission risk
in acute HIV have not been characterized.
Characterization of viral genotype, phenotype, and drug susceptibility of recently infected persons provides sentinel data
on the effect of increased antiretroviral use on transmitted viruses. The prevalence of genotypic resistance among newly infected persons is reported to be 10%–16% for zidovudine resistance and 4%–26% for protease mutations [15–17]. A study
of phenotypic resistance suggested that 26% of seroconverters
had a modest (2.5–10-fold) reduction in HIV susceptibility to
>1 drugs tested [18].
Prospective cohorts of persons recently infected by HIV can
contribute to our understanding of behavioral and biologic risk
factors associated with transmission and the natural history of
early HIV infection. From 1995 to 1998, the domestic sites of
the National Institutes of Health–funded HIV Network for
Prevention Trials (HIVNET) enrolled 103 seroconverters, primarily from the HIV Vaccine Preparedness Study (VPS), into
a natural history study of early HIV-1 infection, which provides
longitudinal virologic data on prospectively identified seroconverters, the relationship of plasma and genital tract virus load
in early HIV infection, the prevalence of genotypic resistance
during increasing utilization of protease inhibitor–containing
regimens, and the feasibility of obtaining pretreatment virus
load and CD4 cell counts for vaccine efficacy trial end points.
Subjects and Methods
Study population. From April through November 1995, 4892
HIV-1–seronegative persons were recruited for the HIVNET VPS
from 8 US cities (Boston, Chicago, Denver, New York, Philadelphia, Providence, RI, San Francisco, and Seattle). Men who had
sex with men (MSM), injection drug users (IDUs), and women at
heterosexual risk were recruited; eligibility criteria, methods of recruitment, and characteristics of the HIVNET VPS have been reported elsewhere [19]. Subjects were offered enrollment in the HIVNET Infected Participant Cohort (IPC) if they were prospectively
identified as newly infected with HIV-1 and had a documented
HIV-negative test result in the prior 7 months (either from the VPS
or from an HIVNET-approved cohort study, primarily the Jumpstart Vaccine Preparedness Cohort [20], or after the conclusion of
VPS, when participants continued to be HIV tested at the site or
enrolled in subsequent HIVNET trials). At the enrollment and
JID 2001;183 (1 January)
semiannual follow-up visits, VPS participants received HIV pretest
counseling, underwent phlebotomy for HIV testing, were weighed,
and responded to structured questionnaires about risk behaviors,
STDs, and retroviral syndrome symptoms in the prior 6 months.
The questions were administered by trained interviewers. All risk
behavior and clinical data were collected for the prior 6 months.
Study procedures. At the IPC enrollment visit, subjects were
interviewed about symptoms, STDs, and risk behaviors with HIVpositive and HIV-unknown serostatus partners. To capture the temporal pattern of risk behaviors and retroviral syndrome symptoms,
interviewers used a calendar-based method to ascertain symptoms
and risk behaviors during each week of the potential “seroconversion period” (3 months before the last negative HIV antibody
test result until the first positive HIV test result). Risks were classified hierarchically, with shared needles as the highest, followed
by sexual risk behaviors, based on per-contact risk estimates of
specific sexual behaviors [21, 22], from most to least risky. Clinicians were asked to estimate the time of seroconversion, on the
basis of timing of symptoms and high-risk behaviors.
Clinicians performed a physical examination, including weight,
and referred subjects with signs or symptoms of an STD or opportunistic infection for medical care. Routine STD testing at the
initial IPC visit included vaginal wet mount examination for vaginitis, rapid plasma reagin testing and confirmatory treponemal
antibody testing for syphilis (available for 92 subjects), and ligase
chain reaction testing for Neisseria gonorrhoeae and Chlamydia
trachomatis from first voided urine specimens and from either endocervical swabs (10 of 14 female subjects) or rectal swabs (performed on the first 25 MSM seroconverters). Seroconverters were
referred to local primary HIV infection treatment studies, primary
medical care, and psychosocial services. IPC participants were seen
1 month after enrollment and every 3 months thereafter for <3
years and were interviewed about risk behaviors, STDs, symptoms,
opportunistic infections, and antiretroviral use.
At each visit, blood samples were obtained for plasma RNA
levels, virus isolation, and lymphocyte subset testing, and men were
asked to provide semen samples. Semen was processed within 2 h
of collection and was centrifuged at 4000 g for 10 min, and the
supernatant was frozen at 2707C. For female participants, clinicians obtained cervical samples with Sno-strips (Chauvin Pharmaceuticals) at the same visit as specimens for PVL. Endocervical
samples were collected by placing 3 absorbent Sno-strips into the
cervical os until secretions wicked to the shoulder of the Sno-strips;
these were placed into guanidine thiocyanate and frozen at 2707C.
Laboratory methods. HIV-1 infection was diagnosed by repeatedly reactive HIV-1 EIA and confirmatory Western blot testing
at the participating sites, confirmed by the HIVNET Central Laboratory. PVL was assayed by HIV-1 reverse transcriptase–polymerase chain reaction (RT-PCR; Roche Amplicor), according to
the manufacturer’s instructions, with a limit of detection of 200
copies/mL, and, after May 1998, by the more sensitive Roche RTPCR assay (limit of detection, 50 copies/mL). Seminal and cervical
virus loads (SVLs and CVLs) were assessed by Amplicor RT-PCR
(limit of detection, 200 copies/mL), and, after May 1998, by the
NucliSens assay (Organon Teknika), which has increased sensitivity
because of the removal of inhibitors from seminal plasma by a
silica extraction step [23–26]. The NucliSens assay has a limit of
detection of 400 copies/mL (or 1000/copies/mL if sample input is
JID 2001;183 (1 January)
Primary HIV, Natural History, and HIV in Semen
!200 mL). Available earlier semen and cervical samples were repeat
tested by NucliSens.
Lymphocyte subsets were measured by flow cytometry on fresh
samples. Virus isolation was performed by standard coculture
methods, in which 5 3 10 6 peripheral blood mononuclear cells
(PBMC) of each participant was mixed with an equal number of
PBMC from seronegative donors and activated with phytohemagglutinin for 72 h [27]. Cultures were maintained at 377C and 5%
CO2 for <30 days and monitored weekly for the production of p24
antigen. Supernatant aliquots from p24 antigen-positive cocultures
were used to inoculate log-phase cultures of MT-2 cells that were
then monitored weekly for syncytium-inducing (SI) formation. Heteroduplex mobility assays were utilized for genotyping the initial
virus isolate [28].
Antiviral genotypic resistance testing. The first available plasma
specimens after seroconversion were assayed for genotypic resistance by using high-density arrays of nucleotide probes (Affymetrix). We used phylogenetic analysis, to monitor for possible contamination during specimen processing or PCR amplification [29].
Genotypic resistance was assessed by population sequencing of the
entire protease (PR) gene and the first 242 codons of the gene
encoding RT [30]. Extracted RNA was fluorescein labeled with
dUTP and sequenced by hybridization to high-density arrays, as
described elsewhere [31]. Sequences from different subjects were
aligned and manually edited, and neighbor-joining phylogenetic
trees were used to seek evidence of epidemiologic linkage between
subjects and/or laboratory contamination. Mutations associated
with resistance to antiretroviral drugs were identified for each person [32, 33]. Assays were run in duplicate on 16 specimens with
identical results.
CCR5 genotype analysis. The CCR5 D32 genotype was determined, as described elsewhere [34], by performing PCR on
PBMC with primers for the 738–760 and 962–938 bp that span the
32-bp deletion, yielding a 0.225-kb amplicon for a wild-type allele
and a 0.192-kb amplicon for a D32 allele.
Data analysis. The time of seroconversion was estimated as
the midpoint between the last negative and first positive HIV test
results. We used x2 tests to assess differences between groups, rank
tests for differences in medians, and Student’s t tests for differences
in means. The time from seroconversion to the initiation of antiretroviral medications was assessed by Kaplan-Meier curves. Rates
of opportunistic infections were computed by using Poisson regression to model the number of events observed during the followup time, counting only the first occurrence of each infection. To
assess recall bias in symptom reporting among seroconverters, we
compared individual symptom reporting from the last visit of seroconverters first identified in the VPS (when they were unaware that
they were HIV positive) with symptom reporting at IPC enrollment.
Because the IPC data collection instrument recorded the timing of
symptoms, we were able to compare symptom reporting from both
studies for the 6 months before the subject’s first HIV-positive test
result. We used the McNemar test to assess the concordance of
reported symptoms lasting >3 days during the 6 months before
the first HIV-positive test result.
In analyses with virus load as a continuous response, values lower
than the detection limit were assigned a value of half the detection
limit. Plasma and semen specimens were analyzed as paired samples
if collected within 21 days. Because of the number of results below
25
the detection limit, the nonparametric Spearman rank correlation
was used to assess correlations between genital and PVL. PVLs and
SVLs were modeled as a log10 response, and virus load data and
CD4 cell counts obtained before initiation of antiretrovirals were
modeled longitudinally with a linear mixed effects model fitted by
maximum likelihood. Linear mixed effect methods model the mean
population response as linear in time but allow random effects, to
account for repeated measurements from individuals when estimating
population-fixed effects [35]. Covariates analyzed in these models
included symptoms consistent with the acute retroviral syndrome,
fever >7 days, seeking medical care during seroconversion (the latter
as surrogates of more severe retroviral syndromes), any SI virus
within the first year, and CCR5 genotype.
Results
Between April 1995 and August 1998, 103 recent seroconverters were enrolled in the IPC. During the VPS, 74 (81%) of
the 91 persons prospectively identified as HIV infected and
eligible were enrolled in the HIVNET IPC. An additional 29
seroconverters were prospectively identified through other HIVNET studies: 20 were identified from prospective cohort studies
in operation at VPS sites (e.g., the Jumpstart Vaccine Preparedness Cohort), and 9 were identified after the conclusion of
the VPS. Of the 103 seroconverters, 83% were MSM, 4% were
male IDUs, and 14% were women, of whom 6 were reported
to be IDUs, and 8 reported only heterosexual activity. MSM
were significantly younger than male IDUs and women, were
more likely to be white, had higher education levels, and were
more likely to have private health insurance (P ! .001 ; table 1).
Median time from estimated seroconversion to IPC enrollment was 4 months. Eight seroconverters (all MSM) were diagnosed at the time of a positive ELISA and an indeterminate
Western blot, with subsequent Western blot–confirmed seroconversion. Eleven seroconverters first tested positive at unscheduled interim study visits that were initiated by participants
for high-risk exposures (n p 6), possible retroviral symptoms
(n p 1), or both (n p 3); one was tested for other reasons.
Three persons with interim testing initially had indeterminate
Western blot results and were seroconverting. The IPC had a
median of 10 visits (interquartile range [IQR]: 6–12 months)
during a median follow-up of 29 months (IQR: 18–30 months).
Risk behavior and STDs during the seroconversion period.
Behavioral risk factors and clinical features of seroconversion
were assessed 3 months before the last seronegative test result
through the first seropositive test result; the median duration for
this seroconversion period was 9.1 months. Compared with seroconverters from other risk groups, MSM reported having a
higher median number of sex partners, particularly partners of
unknown HIV serostatus (table 1). Only 9 seroconverters reported a single HIV-infected partner in the seroconversion period.
Complete calendar-based risk data were available for 98 seroconverters (figure 1) and were rank-ordered by high-risk injection drug use (sharing needles or equipment), followed by sex-
26
Celum et al.
JID 2001;183 (1 January)
Table 1. Demographics, risk behaviors, and recent sexually transmitted diseases (STDs) among
103 Human Immunodeficiency Virus (HIV) Network for Prevention Trials seroconverters.
MSM
(n p 85)
Characteristic
Median age, years (range)
Race/ethnicity
White
African American
Hispanic
Other/mixed
Education
Less than high school
High school graduate/GED
More than high school
b
Health insurance
Private
Medicare/Medicaid
Other
None
c
Median no. (IQR) of sex partners during seroconversion period
Total partners
HIV-positive partners
Partners of unknown serostatus
Monogamy status
1 Partner
1 HIV-positive partner
Injection drug use
Hierarchical risks with HIV-positive or unknown serostatus
c,d
partners in seroconversion period
Shared needles/injection equipment
Unprotected receptive anal sex
Unprotected insertive anal sex
Unprotected vaginal sex
Unprotected receptive oral sex
Protected anal and/or vaginal sex
No identifiable risk
c
Self-reported STDs in seroconversion period
Any STD
Herpes/anogenital lesions
Gonorrhea
Nongonococcal/chlamydial urethritis
Vaginal discharge or PID
Laboratory-diagnosed STDs at IPC enrollment,
no./no. tested (%)
Early infectious syphilis
Urethral/cervical gonorrhea
Rectal gonorrhea/chlamydia
Trichomonal vaginitis
Male IDUs
(n p 4)
Women
(n p 14)
a
40 (34–45)
40 (25–50)
a
0
1 (25.0)
3 (75.0)
0
2 (14.3)
7 (50.0)
5 (35.7)
0
a
2 (50.0)
2 (50.0)
0
7 (50.0)
5 (35.7)
2 (14.3)
a
0
2 (50.0)
0
2 (50.0)
0
10 (76.9)
0
3 (23.1)
32 (20–55)
56
7
14
8
(65.9)
(8.2)
(16.5)
(9.4)
1 (1.2)
14 (16.5)
70 (82.4)
38
2
6
21
(56.7)
(3.0)
(9.0)
(31.3)
a
1.0 (1–2)
0.5 (0–1)
05 (0–1)
1.5 (1–3)
0.0 (0–1)
1.0 (0–3)
8 (9.4)
5 (5.9)
a
5 (5.9)
3 (75.0)
1 (25.0)
4 (100.0)
6 (42.9)
3 (21.4)
6 (42.9)
4 (4.8)
54 (65.1)
7 (8.4)
NA
14 (16.9)
2 (2.4)
2 (2.4)
2 (66.7)
NA
0
1 (33.3)
NA
0
0
4 (33.3)
1 (8.3)
NA
6 (50.0)
NA
0
1 (8.3)
22
11
5
5
0
0
0
0
3 (25.0)
1 (8.3)
1 (8.3)
NA
3 (25.0)
10.0 (4–35)
1.0 (0–1)
8.0 (3–24)
a
(26.5)
(12.6)
(6.0)
(6.0)
NA
1/73 (1.4)
1/71 (1.4)
3/26 (11.5)
NA
NA
0/4
0/3
0/1
NA
1/13 (7.7)
0/11
0/4
2/10 (20.0)
NOTE. Data are no. (%), unless otherwise noted. GED, general education diploma; IDU, injection drug
user; IPC, Infected Participant Cohort; IQR, interquartile range; MSM, men who have sex with men; NA, not
applicable; PID, pelvic inflammatory disease; STD, sexually transmitted disease.
a
P ! .001 for difference in MSM vs. other risk groups (male IDUs and women combined). Kruskal-Wallace
test was used for differences in medians, x2 test was used for differences in grouped data, and Fisher’s exact test
was used for differences in the 3 risk groups in reported injection drug use in the prior 6 months.
b
Data on health insurance not available for 17 MSM and 1 woman who did not complete the Vaccine
Preparedness Study.
c
Seroconversion period is defined as assessment period spanning 3 months before last negative test result to
first HIV-positive test result. Data are presented for 98 IPC seroconverters (83 MSM, 3 male IDUs, and 12
women) for whom complete calendar-based risk was available.
d
Risks are presented as a hierarchy; subject is shown once by highest risk behavior reported in seroconversion
period.
ual risk behaviors with HIV-positive partners or partners of
unknown serostatus (table 1). Among the 83 MSM seroconverters, injection drug use with sharing of equipment was rare
(5%), and unprotected receptive anal sex with an HIV-positive
or unknown partner was reported by almost two-thirds. Four-
teen MSM reported unprotected receptive oral sex as their highest risk, 12 of whom also reported protected anal sex and may
have not recognized or reported condom breakage or slippage;
thus, oral sex may not have been their only route of exposure.
Injection drug use was reported by all 4 male IDUs and 6
Figure 1. Unprotected risk behavior (anal or vaginal sex or shared needles) reported by seroconverters during seroconversion period. Each
horizontal line represents behavior of 1 subject; length of line is duration of seroconversion period. Risk behaviors reported in each week are
plotted as symbols (v; unprotected anal or vaginal sex with known human immunodeficiency virus (HIV)–positive partner or partner of unknown
status or shared needles/injection equipment). Last HIV-seronegative test result is shown as vertical line. Seroconversion period is defined as 3
months before last negative test result to first HIV-positive test result. IPC, Infected Participant Cohort.
28
Celum et al.
women with complete risk behavior data, only 6 of whom reported sharing injection equipment. Most female seroconverters
reported sexual risks; 1 reported unprotected anal sex, and 6
reported unprotected vaginal sex with HIV-positive or unknown serostatus sex partners.
Most participants reported multiple high-risk behaviors with
HIV-positive and unknown serostatus partners; figure 1 displays risk behaviors for each week in the seroconversion period
for the 98 persons with complete calendar-based risk data, ordered from those reporting the most to those with the least
frequent unprotected exposures. About one-third of seroconverters reported frequent high-risk exposures (>9 weeks with
episodes of unprotected vaginal or anal sex or shared injection
equipment during the seroconversion period), one-third had
occasional high-risk exposures (2–8 weeks with such exposures),
and the remaining seroconverters reported rare high-risk activity (0 or 1 week with such exposures). About 16% reported
only protected sexual and injection exposures, which are not
included in figure 1.
STDs during the seroconversion period were self-reported by
27%, most commonly genital herpes or symptoms of herpes
(e.g., anogenital sores). At IPC enrollment, 7 seroconverters
had laboratory-diagnosed STDs (table 1), including 2 with reactive syphilis test results consistent with early infectious syphilis, 4 MSM with gonorrhea and/or chlamydia (primarily rectal
infections), and 2 women with trichomonal vaginitis. In total,
29% of the cohort either self-reported STDs during seroconversion or presumptive STDs or laboratory-confirmed asymptomatic STDs at IPC enrollment. Seven seroconverters were
referred by the IPC clinician for STD evaluations because of
reported STD symptoms or because they had clinical findings
at IPC enrollment, but results of the evaluations were not consistently reported to study clinicians.
Symptoms of acute retroviral illness during the seroconversion
period. Information on symptoms during the seroconversion
period was available for 101 subjects, 85 of whom reported >1
symptom lasting >3 days (table 2). The most frequently reported symptoms persisting >3 days were fatigue (57 subjects)
and fever (reported by 56 subjects; 23 reported >7 days of
fever). Other common symptoms lasting >3 days were fatigue,
pharyngitis, myalgias, lymphadenopathy, and headache. Rash
lasting >3 days was reported by only 16 seroconverters. Among
those reporting symptoms, research clinicians had difficulty in
timing seroconversion in 32% of cases because symptoms were
thought to be unlikely to be related to HIV, multiple symptom
episodes were reported, or the participant had difficulty recalling dates of symptoms.
In comparing the concordance of retroviral syndrome symptom reporting before and after subjects learned of their positive
HIV results for the 71 subjects with such data, we found that
participants were significantly more likely to report fever,
sweats, headache, nausea, lymphadenopathy, and myalgias after learning of their positive result (at the initial IPC interview)
JID 2001;183 (1 January)
Table 2. Symptoms, medical care, and activity level during seroconversion period.
Symptom or activity
Symptoms of >3 days during
a
seroconversion (n p 101)
Any symptom
Fatigue
Fever
Pharyngitis
Sore muscles
Lymphadenopathy
Headache
Diarrhea
Nausea
Meningismus
Photophobia
Rash
Vomiting
Oropharyngeal sores
Activity level and medical care during
a
seroconversion (n p 102)
Changed usual activities because
of illness
Missed work because of illness
Sought medical care because of
symptoms
Provider suspected acute HIV,
among those who sought
medical care
Hospitalized during seroconversion
period
Seroconverters,
no. (%)
85
57
56
43
39
36
33
27
26
20
16
16
13
6
(84.2)
(56.4)
(55.4)
(42.6)
(38.6)
(35.6)
(32.7)
(26.7)
(25.7)
(19.8)
(15.8)
(15.8)
(12.9)
(5.9)
Median duration,
days (IQR)
9.0
5.0
7.0
7.0
7.0
11.0
9.0
8.5
10.0
12.5
8.0
7.0
11.0
(5–29)
(4–10)
(5–10)
(4–16)
(4–14)
(4–16)
(4–20)
(4–15)
(7–17)
(9–33)
(6–14)
(4–10)
(6–12)
70 (68.2)
59 (57.8)
50 (49.0)
8/50 (16.0)
12 (11.8)
NOTE. HIV, human immunodeficiency virus; IQR, interquartile range.
a
The seroconversion period is defined as assessment period spanning 3 months
before last negative test result to first HIV-positive test result.
than before (at the time of their last VPS visit; P ! .01 for each
individual symptom by McNemar test). Of interest, although
only 19% of seroconverters reported weight loss >5 lbs (2.27
kg), clinicians documented such weight loss in 39% of those
whose weight was measured at their last VPS and IPC enrollment visits.
Information on medical care during the seroconversion period
was available for 102 subjects. Symptoms were severe enough
for 68% to change their daily activities and for 57% to miss work.
Almost half (49%) sought medical care for their symptoms, and
seeking care was strongly associated with fever lasting >3 days
(36 reported fever >3 days among 48 who sought care, compared
with 19 of 52 who did not seek care; P ! .001). Eight (18.2%) of
the 44 MSM and 0 of the 6 non-MSM who sought medical care
reported that their provider suspected acute HIV infection. Providers were more likely to presumptively diagnose acute HIV
infection in MSM if the participant reported fever of >7 days
(5 of 13 MSM with prolonged fever vs. 2 of 30 without; P p
.009) or a rash of >3 days (5 of 12 MSM with rash vs. 2 of 29
without; P p .005). Other presumptive diagnoses included upper
respiratory infections, “flu” and viral syndromes, sinusitis, and
streptococcal pharyngitis.
Antiretroviral use and genotypic resistance. Antiretroviral use
was reported by 72 subjects at some point during study follow-
JID 2001;183 (1 January)
Primary HIV, Natural History, and HIV in Semen
up; median time to initiating antiretrovirals was 9.4 months after
learning their HIV-positive result. By survival analysis, time to
initiation of antiretrovirals did not differ by year of seroconversion (1995–1998). MSM were more likely to be treated and initiated therapy sooner after seroconversion than women (median,
8 vs. 18 months; P p .02); none of the 4 male IDUs initiated
antiretrovirals during follow-up. By survival analysis, 57% of the
cohort was estimated to initiate antiretroviral treatment within
the first year of an HIV-positive test result; 25% initiated protease
inhibitor–containing regimens, and 32% had regimens that did
not include a protease inhibitor.
Drug resistance genotyping was attempted on pretreatment
plasma specimens taken from 80 subjects at their first postseroconversion visits. PCR amplification for genotyping failed for
8 specimens, 2 with no PVL results available, 3 with !1000
copies/mL, and 3 with 5000–18,000 copies/mL. Specimens from
these subjects were not available for repeat amplification attempts by more sensitive nested PCR methods. Genotyping
assays were successfully performed for the remaining 72 subjects (90%), and no sequences clustered together with 13% similarity. Seven seroconverters (9.7%) had markers of resistance
to nucleoside RT inhibitors (nRTIs), and 2 (2.8%) had resistance
to non-nRTIs [32]. The most common RT mutations were associated with zidovudine resistance, including RT M41L
(n p 2), K70R (n p 2), K219Q (n p 2), and T215Y (n p 1),
which is also associated with resistance to stavudine [36]. One
person had the PR V82A mutation, a primary resistance mutation associated with early virologic failure of ritonavir and
indinavir, but insufficient to cause detectable protease inhibitor
cross-resistance without other key protease mutations [33, 37,
38]. An additional 11 (15.3%) had common protease polymorphisms that can contribute to protease inhibitor resistance in
the presence of primary mutations, but which have no known
clinical importance otherwise. We observed no significant differences in genotypic resistance by site, year of enrollment, or
risk group.
Viral clade and phenotype. All 103 seroconverters had clade
B virus by heteroduplex mobility assay analysis. Of the 93 subjects with a positive HIV culture at enrollment, 5 had an SI
phenotype within 9 months of enrollment and 88 had non-SI
(NSI) phenotypic viruses throughout follow-up. Three of the
5 seroconverters with an SI phenotype had a predominant SI
phenotype at their first visit. One of these was homozygous for
the 32-bp CCR5 deletion (D32/D32); the remaining 4 had wildtype CCR5 (wt/wt) genotype by PCR.
PVL: baseline and natural history. Median initial PVL was
25,800 copies/mL (IQR: 6947–49,462) among the 89 subjects
with pretreatment samples obtained a median of 4 months after
seroconversion. Only 1 treatment-naive subject had undetectable PVL at his first postseroconversion visit (3 months after
seroconversion). No differences were found between 76 men
and 13 women for their initial pretreatment PVL; male seroconverters had a median of 25,797 copies/mL (range, !200–
29
262,281 copies/mL) and female seroconverters a median of
23,811 copies/mL (range, !200–215,008 copies/mL). Eighty
participants (78%) had >2 PVL measurements obtained before
starting antiretroviral therapy. Of these 80 subjects, 12 (15%)
had an initial virus load of 1100,000 copies, but only 3 of these
12 had a subsequent drop in PVL >50%, which is suggestive
of a transition from peak virus load to “set point.” Of the 68
whose initial PVL was !100,000 copies/mL, a lower proportion
(10 [15%] of 68) had a 150% drop in PVL (P p .06).
Longitudinal modeling of PVL before antiretroviral therapy
revealed a small but significant increase in mean log10 PVL after
seroconversion, with an estimated mean virus load 6 months
after seroconversion of 4.34 log10 copies/mL and estimated increase of 0.12 5 0.05 (SE/year) log10 copies/mL. No significant
differences were found in initial PVL (intercept) or change in
PVL over time when adjusted for baseline variables, including
surrogates of a more severe retroviral syndrome (i.e., fever >7
days, any virus-like symptom, and seeking medical care during
seroconversion), CCR5 genotype, or SI phenotype during the
first year of follow-up. However, these analyses have limited
power because of the relatively short duration of follow-up.
Figure 2 depicts PVL by type of antiretroviral use at the time
of sample collection: PVL was lowest for samples obtained from
persons receiving HAART (median, not detectable), intermediate for samples from subjects taking antiretrovirals that did
not include a protease inhibitor (median, 1320 copies/mL), and
highest for samples from subjects not receiving any antiretroviral therapy (median, 24,400 copies/mL; P ! .001). Thirtythree samples were obtained when the participant had been
taking the antiretroviral regimen !30 days; only 9 of these 33
had PVL 150,000 copies/mL, and the median values did not
change significantly when the analyses were restricted to those
taking antiretrovirals 11 month. Initial PVL was highly variable, with a range of 13 logs among untreated persons at comparable times from seroconversion. The intraperson variability
in PVL was ∼2-fold, on the basis of a residual SD of 0.34 for
log10 PVL.
SVL: baseline and natural history. We collected >1 sample
from 75 (84%) of 89 male seroconverters enrolled in the IPC.
Among initial semen samples obtained from 60 antiretroviralnaive men, median SVL was 545 copies/mL (IQR: ! 400–6000),
and 40% had undetectable seminal plasma RNA. Figure 2 depicts SVL over time, by antiretroviral use at the time of sample
collection. SVL was lowest among samples from men receiving
HAART (median, 200 copies/mL; 92% undetectable), intermediate for samples from men taking antiretroviral regimens
that did not include a protease inhibitor (median, 200 copies/
mL; 82% undetectable), and highest for samples from men not
receiving any antiretroviral therapy (median, 750 copies/mL;
42% undetectable; P ! .001 for differences among the 3 groups).
Longitudinal modeling of pretreatment SVL did not reveal significant change in mean log10 SVL over time and, as with PVL,
no significant differences were found in longitudinal SVL when
30
Celum et al.
JID 2001;183 (1 January)
Figure 2. Plasma and semen virus load, by months since seroconversion and antiretroviral use. Virus load is stratified by type of antiretroviral
use at time of blood collection, defined as no therapy, combination antiretroviral therapy (ART) that did not include a protease inhibitor, and
highly active antiretroviral therapy including a protease inhibitor (HAART). Roche reverse transcriptase–polymerase chain reaction (RT-PCR)
assay was used on plasma (limit of detection, 200 copies/mL). Most samples with undetectable virus by that assay were also tested by the more
sensitive Roche RT-PCR assay (limit of detection, 50 copies/mL). Seminal plasma was assayed for virus load by the NucliSens assay (Organon
Teknika; limit of detection, 400 copies/mL or 1000 copies/mL if sample input was !200 mL). 1, Samples with detectable virus load; V, undetectable
virus load samples. Samples with undetectable virus load are depicted on the plots as half the limit of detection. Median virus load is indicated
by horizontal lines. Of the samples from subjects on antiretroviral therapy, all but 33 subjects had been on therapy >30 days; only 9 had plasma
virus loads 150,000 copies/mL. Median values for plasma and semen virus loads did not change significantly when restricted to those taking
antiretrovirals for 11 month.
adjusted for baseline variables. However, there was greater average intraperson variability for SVL than for PVL; the residual
SD for pretreatment SVL was 0.64, corresponding to a 4-fold
intraperson variability in SVL (vs. a 2-fold within-person variability in PVL), which reduces statistical power for detecting
trends or differences.
Relationship between PVL and SVL. On average, SVL was
1.3 log10 lower than PVL. For samples obtained before antiretroviral use, men with high PVL were significantly more likely to
have detectable seminal RNA than those with lower PVL (figure
3). When PVL was 150,000, 67% of corresponding seminal
plasma samples had detectable RNA levels, compared with 61%
when PVL was 10,000–50,000 and 40% when PVL was !10,000
(P p .02). Paired PVL and SVL for samples obtained before
initiation of antiretrovirals were only modestly correlated (r p
.28; 95% confidence interval [CI], 0.16–0.42; P ! .001). We could
not correlate SVL with PVL in men taking antiretrovirals, because 88% of such semen samples had undetectable virus load.
Of the 54 men who provided >2 semen specimens while on
antiretroviral therapy, 18 (33%) had detectable SVL at least once
and 4 had persistently undetectable PVL. Even when PVL was
!5000 copies, a significant minority of samples had detectable
RNA in seminal plasma: 32% (7/22 samples) from 5 of 16 men
not taking antiretrovirals, 12% (7/60 samples) from 6 of 32 men
taking antiretrovirals that did not include a protease inhibitor,
and 6% (8/129 samples) from 7 of 52 men on a protease inhibitor–containing regimen (P p .001).
CVL. Of the 14 female seroconverters enrolled in the IPC,
cervical Sno-strip results were available for 20 samples from 6
women not on antiretroviral treatment and for 15 samples from
4 women on antiretroviral therapy (none on protease inhibitor–
containing regimens). In all, 60% of women had undetectable
JID 2001;183 (1 January)
Primary HIV, Natural History, and HIV in Semen
31
Figure 3. Relationship of plasma and semen virus load, by antiretroviral use. Corresponding plasma and semen samples are shown by type
of antiretroviral used at time of the sample collection: none, combination therapy that did not include a protease inhibitor with antiretroviral
therapy (ART), and highly active antiretroviral therapy including a protease inhibitor (HAART). Plasma virus load (PVL) was tested by Roche
reverse transcriptase–polymerase chain reaction (RT-PCR) assay for PVL (detection limit, 200 copies/mL); most samples with !200 copies/mL
were tested by the more sensitive Roche RT-PCR assay (detection limit, 50 copies/mL). Seminal plasma was assayed for virus load by NucliSens
assay (Organon Teknika; detection limit, 400 copies/mL or 1000 copies/mL if sample input was !200 mL). v, Paired samples in which both
plasma and semen samples had detectable virus load; V, virus undetectable in plasma but detectable in semen; 1, human immunodeficiency virus
(HIV) undetectable in semen but detectable in plasma; %, HIV undetectable in both plasma and semen. All but 33 patients on antiretroviral
therapy had been on therapy 130 days; of these, 9 had PVL 150,000 copies/mL.
CVLs (12 of 20 samples from women not taking antiretrovirals
and 9 of 15 samples from women taking antiretrovirals). For
the 14 samples with a detectable virus load, 13 had >20,000
copies/mL, and 9 had virus loads >200,000 copies/mL. We had
too few samples to assess the relationship of CVL and PVL
for women stratified by antiretroviral therapy.
Early disease progression: CD4 cell counts and clinical
events. Pretreatment CD4 cell counts varied considerably at
the first postseroconversion visit, with a mean absolute count
of 602 5 25 CD4 cells among 88 subjects. By use of linear mixed
effects for longitudinal modeling of pretreatment CD4 cells, we
found that early SI phenotype and heterozygous CCR5 (D32/
wt) genotype were significantly associated with CD4 cell count.
Although those with NSI viral phenotype and wild-type CCR5
genotypes were estimated to have mean CD4 cell counts 6
months after seroconversion of 585 (95% CI, 542–628) and a
mean decrease of 98 (95% CI, 76–120; P ! .001) CD4 cells per
year, the 8 CCR5 heterozygotes (D32/wt) had 238 more CD4
cells (95% CI, 52–424; P p .002), and the 5 with early SI phenotype had 244 fewer CD4 cells (95% CI, 101–357; P p .012),
on average, 6 months after seroconversion. No differences in
rate of subsequent CD4 cell decline were detected for either of
these factors.
During follow-up, 1 woman died of complications related to
an Epstein Barr virus–associated lymphoma in the first year
after seroconversion, and 1 man committed suicide 20 months
after his positive HIV test result. Among 101 seroconverters
with >1 follow-up visit, the incidence of opportunistic infec-
tions was 10.8/100 person-years of follow-up. The incidence of
opportunistic infections that occurred before antiretroviral initiation was 14.7/100 person-years in 11 of 89 people. The most
commonly reported infections were oral candidiasis (n p 15)
and herpes zoster (n p 12 ). Eight AIDS-defining illnesses were
reported during follow-up, including chronic herpes simplex
infections (n p 4), Pneumocystis carinii pneumonia (n p 2), tuberculosis (n p 1), and candidal esophagitis (n p 1).
Discussion
The HIVNET IPC provides comprehensive behavioral, clinical, and laboratory data for a diverse group of men and women
in the United States who were newly HIV-infected between 1995
and 1998. HIVNET seroconverters were prospectively identified
in a vaccine preparedness cohort of high-risk persons with semiannual testing and had a different profile of risk behaviors than
did referral-based seroconverter cohorts identified because of
isolated high-risk exposures or symptoms. In addition, this prospectively identified cohort of seroconverters enables analysis
of recall bias of retroviral symptoms by comparing symptom
reporting before and after learning of HIV-positive results and
provides relevant virologic and immunologic data for planning
the evaluation of HIV vaccines on viral kinetics and set point
in breakthrough infections that occur in vaccine efficacy trials.
We found that most seroconverters had multiple potential
exposures, particularly MSM, and that few (9%) had a single
HIV-positive partner in the 9 months before their first HIV-
32
Celum et al.
positive result. This proportion is considerably lower than that
reported by others [6] and suggests that recruitment of highrisk persons for US HIV prevention and vaccine trials should
not rely on recruitment of HIV-discordant couples and that it
is often difficult to identify the source partner. Most MSM
seroconverters reported multiple episodes of unprotected anal
sex with an HIV-positive or unknown serostatus partner. Although oral sex is a relatively frequent mode of HIV transmission among MSM [6], our study suggests that most men
reporting unprotected receptive oral sex also reported protected
anal sex. As in other cohort studies that rely on self-reported
behavioral data, some seroconverters may not have recognized
condom failure and others may have overreported condom use,
which could result in overattribution of HIV transmission to
oral sexual exposure. Injection drug use was reported by 15%
of the cohort, and 10% reported sharing needles or injection
equipment in the periseroconversion assessment period. Among
the female seroconverters, high-risk sexual activity was more
common than injection drug use.
Most (85%) seroconverters retrospectively reported >1 virus
syndrome–like symptom lasting >3 days in their seroconversion
period. This proportion and the spectrum of the most common
symptoms—fever, fatigue, and pharyngitis—were similar to
those found in other referral-based cohorts [6, 39]. However,
overall only 21% of the HIVNET seroconverters reported rash,
16% for >3 days, which is somewhat lower than the 30%–68%
reported elsewhere from referral-based cohorts [6, 40–42]. Our
comparison of symptom reporting before and after receiving
positive HIV test results indicates either underreporting of nonspecific symptoms during seroconversion or recall bias, with
increased reporting of nonspecific viral symptoms, such as fever,
sweats, headache, and lymphadenopathy, after learning of their
HIV-positive results, which is similar to findings in female seroconverters in Kenya [43]. We did not find an association between fever for >7 days and higher PVL or more rapid disease
progression, as others have reported [39, 44–46]. The reason
for this disparity in findings could be recall bias in reported
frequency or duration of fever or more rapid initiation of treatment of symptomatic seroconverters; however, we found no
difference in time to initiation of antiretrovirals among those
with fever or other symptoms.
Although many symptomatic subjects sought medical care,
their providers rarely made a presumptive diagnosis of acute
HIV infection, a finding similar to those in referral-based cohorts [6]. Providers were more likely to presumptively diagnose
acute HIV among MSM, particularly those with prolonged
fever and rash, than among other symptomatic subjects. The
sensitivity of specific individual symptoms or >2 symptoms is
relatively low in predicting acute HIV infection [43]. Thus, to
facilitate early diagnosis of acute HIV infection, educational
efforts must continue to emphasize both the nonspecific nature
of acute retroviral syndrome symptoms and the need for providers to ask about risk behavior and to consider the diagnosis
JID 2001;183 (1 January)
in persons at risk, even in the absence of specific symptoms,
such as rash.
We observed HIV with a predominant SI phenotype in 5 subjects in the first 9 months after enrollment, 3 of whom had initial
and persistent SI virus. Two had wild-type CCR5 genotype, and
1 was homozygous for the 32-bp deletion of CCR5. This is the
seventh published such case demonstrating that the D32/D32 genotype is not completely protective, likely because of infection
with viruses that use CXCR4 receptors [47–52]. The 5 persons
with predominant SI phenotype early after seroconversion had
lower pretreatment CD4 cell counts, whereas, before antiretroviral initiation, the 8 subjects with CCR5 heterozygotes (D32/wt)
had higher CD4 cell counts before antiretroviral initiation than
did those with wild-type CCR5 genotype. This finding of more
CD4 cells among heterozygotes is biologically plausible and consistent with other reports [53–60].
We did not observe very high virus loads in the first weeks
after seroconversion or a high proportion with obvious “inflection points” in plasma viremia, as reported in other referralbased cohorts [7], because of semiannual HIV testing in the
VPS, which resulted in later identification of seroconverters.
We observed relatively stable pretreatment virus load among
the HIVNET seroconverters, indicating that most had reached
a “virus set point.” The median initial virus load among HIVNET seroconverters (obtained an average of 4 months after
seroconversion) was comparable to that in other cohorts that
showed that initial serum or plasma HIV RNA level in the first
3–7 months after seroconversion is highly predictive of time to
development of AIDS [61–63]. We did not find a difference in
average initial pretreatment plasma viremia between men and
women, as others have reported [64, 65], but our power to detect
a difference was limited, with only 14 female seroconverters.
We found a modest correlation (r p .28; 95% CI, 0.16–0.42)
between virus load in seminal plasma and blood plasma in
treatment-naive HIVNET seroconverters, which is somewhat
lower than that reported (r p .5–.6) among untreated chronically infected persons [10, 23, 66–68]. Average SVL was 1.3
log10 lower than PVL among men not on antiretroviral therapy.
Although seminal plasma RNA was detected more frequently
among men with higher blood plasma RNA levels, it is of note
that we found detectable HIV RNA in semen in 40% of untreated men with low (!10,000 copies/mL) PVL. In addition,
we detected HIV RNA in seminal plasma among a substantial
minority of men taking antiretrovirals: 17% of samples from
men on regimens that did not include a protease inhibitor and
8% of men on HAART, including 7% of semen specimens from
men on HAART whose PVL was !5000 copies. A minority of
these men (4/18) appeared to have genital tract “compartmentalization,” with intermittently or persistently detectable viral
replication in semen with undetectable viral RNA in blood
plasma, which is consistent with previous findings [69].
The implications of these findings for transmission are limited
by uncertainty about whether the main infectious unit is cell-
JID 2001;183 (1 January)
Primary HIV, Natural History, and HIV in Semen
free virus, as we measured, cell-associated virus, or both [12].
Nevertheless, even persons with “undetectable” genital tract or
blood plasma cell-free RNA can have cultivable cell-associated,
potentially infectious virus in semen and blood [70]. Thus, clinicians must continue to counsel HIV-infected persons that they
cannot make assumptions about their level of infectiousness on
the basis of their plasma RNA level or use of antiretrovirals.
A substantial minority (∼30%) of HIVNET seroconverters either reported recent STDs in the seroconversion period or had
clinical findings of an STD or a laboratory diagnosis of an STD
at the IPC enrollment visit. STDs could have affected HIV transmission risk by either increasing infectivity of the source partner,
susceptibility of the HIV-negative partner, or both. We could not
assess the effect of STDs on genital HIV shedding in primary
HIV infection due to timing of genital tract sample collection
with respect to the date of STD diagnoses and the small number
of laboratory-confirmed STDs. However, given the data indicating that some STDs, such as urethral gonorrhea and genital
herpes, increase genital tract HIV shedding in chronic HIV infection [14, 71, 72], STDs could also potentially augment HIV
infectivity during primary HIV infection.
For HIV vaccine efficacy studies, secondary end points of
interest are plasma and genital tract virus load among participants infected during the course of the trial, which will be used
as surrogate markers for the effect of an HIV vaccine on disease
progression and infectivity [2]. These large vaccine trials will
likely be able to afford to collect specimens only on a semiannual basis, which is similar to the collection schedule in the
VPS. Given the powerful effect of HAART in reducing viral
replication, it will be important to obtain several blood and
genital tract measurements after seroconversion, to assess the
effect of vaccination on virus load before treatment is initiated.
Our data indicate that it may be feasible to obtain >2 plasma
measurements before initiation of antiretrovirals, even when
newly infected participants are immediately referred to care and
treatment trials.
Our enrollment period spanned 1995–1998, when HAART was
increasingly promulgated for primary HIV infection. Despite increased publicity about HAART and national treatment guidelines that recommend treatment of primary HIV infection, only
slightly more than half of HIVNET seroconverters initiated antiretroviral therapy within the first year. MSM were significantly
more likely to initiate antiretrovirals than were female or IDU
seroconverters, which may reflect access to care, provider attitudes, or seroconverter willingness to initiate therapy.
Primary HIV-1 drug resistance to all classes of approved
antiretroviral drugs in chronically infected persons and seroconverters has been described elsewhere [15, 16, 18, 73–78].
Overall, 9.7% of the cohort had mutations in the RT gene
associated with resistance to nucleoside analogues, the prevalence of which did not vary by city, risk group, or calendar
year. The prevalence of genotypic resistance we observed is
comparable to recent reports of seroconverters in Europe and
33
the United States [15–17, 79]. We observed a primary protease
mutation in just 1 seroconverter (the PR V82A mutation),
which is considered to be insufficient to cause detectable decreased susceptibility to protease inhibitors [37, 38].
In summary, our findings have relevance to pathogenesis and
treatment studies of acute HIV infection, vaccine efficacy trials,
and HIV prevention programs. We found that seroconverters
often reported multiple episodes of risk behavior in the seroconversion period. Even with increased recognition of primary
HIV infection by health care providers and at-risk persons,
acute HIV was presumptively diagnosed in a minority of the
symptomatic HIVNET seroconverters who sought medical
care, reflecting possible missed opportunities for early treatment
[80–82] and prevention of secondary transmission [3]. Additional efforts to improve recognition of early HIV infection will
be important, to increase the sensitivity and timeliness of this
diagnosis. Even in the era of increased use of antiretrovirals,
we did not find substantial antiretroviral resistance among the
earliest virus isolates, the best available measure of genotypic
resistance in transmitted viruses. We did demonstrate the feasibility of measuring PVL as a surrogate marker of the effect
of HIV vaccines on initial virus load before initiation of antiretroviral therapy. Finally, our finding that genital tract virus
load can be detectable even in the setting of low or undetectable
PVL during early HIV infection may have implications for the
use of therapy as a means of preventing transmission of HIV.
Although the relationship between genital tract virus load and
transmission has yet to be demonstrated, particularly in early
HIV infection, it is possible that genital tract virus load may
represent a more precise marker of transmissibility. Therefore,
both recently infected persons and those with chronic HIV infection must be counseled not to make assumptions about their
potential infectivity on the basis of their PVL. Studies to better
characterize persistence of detectable SVL with low or undetectable PVL are an important priority.
Acknowledgments
We acknowledge the contributions of the investigators, site coordinators, clinicians, and other staff at each HIV Network for Prevention
Trials (HIVNET) site, the participation and dedication of the study
participants, the helpful comments of the HIVNET Manuscript Review
Committee, and the assistance of Tennessee Dickenson (HIVNET Unit,
Seattle) in manuscript preparation.
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