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Screening for HIV: Systematic Review to Update the 2005 U.S. Preventive Services Task Force Recommendation

November 2012
Annals of Internal Medicine 157(10):706-18

DOI:10.7326/0003-4819-157-10-201211200-00007

Source
PubMed

Authors:

Tracy L Dana

Oregon Health & Science University

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A 2005 U.S. Preventive Services Task Force (USPSTF) review found good evidence that HIV screening is accurate and that antiretroviral therapy (ART) for immunologically advanced disease is associated with substantial clinical benefits, but insufficient evidence to determine the effects on transmission or in less immunologically advanced disease. To update the 2005 USPSTF review on benefits and harms of HIV screening in adolescents and adults, focusing on research gaps identified in the prior review. MEDLINE (2004 to June 2012) and the Cochrane Library (through the second quarter of 2012). Randomized trials and observational studies that compared HIV screening strategies and reported clinical outcomes, evaluated the effects of starting ART at different CD4 cell count thresholds and long-term harms, or reported the effects of interventions on transmission risk. 2 authors abstracted and checked study details and quality using predefined criteria. No study directly evaluated the effects on clinical outcomes of screening versus no screening for HIV infection. A randomized trial and a subgroup analysis from a randomized trial found that ART initiation at CD4 counts less than 0.250 × 109 cells/L was associated with a higher risk for death or AIDS-defining events than initiation at CD4 counts greater than 0.350 × 109 cells/L (hazard ratios, 1.7 [95% CI, 1.1 to 2.5] and 5.3 [CI, 1.3 to 9.6]). Large, fair-quality cohort studies also consistently found that ART initiation at CD4 counts of 0.350 to 0.500 × 109 cells/L was associated with lower risk for death or AIDS-defining events than delayed initiation. New evidence from good-quality cohorts with longer-term follow-up confirms a previously observed small increased risk for cardiovascular events associated with certain antiretrovirals. Strong evidence from 1 good-quality randomized trial and 7 observational studies found that ART was associated with a 10- to 20-fold reduction in risk for sexual transmission of HIV. Only English-language articles were included. Observational studies were included. Studies done in resource-poor or high-prevalence settings were included but might have limited applicability to general screening in the United States. Previous studies have shown that HIV screening is accurate, targeted screening misses a substantial proportion of cases, and treatments are effective in patients with advanced immunodeficiency. New evidence indicates that ART reduces risk for AIDS-defining events and death in persons with less advanced immunodeficiency and reduces sexual transmission of HIV. Agency for Healthcare Research and Quality.

Continued Mortality Progression to AIDS/AIDS-Related Events Mortality or Progression to AIDS/AIDS-Related Events

…

. Summary of Evidence

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Continued Limitations Consistency Applicability Summary of Findings for 2012 Update

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Figure. Analytic framework and key questions for screening for HIV in nonpregnant adolescents and adults.

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Figure. Analytic framework and key questions for screening for HIV in nonpregnant adolescents and adults.

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Screening for HIV: Systematic Review to Update the 2005

U.S. Preventive Services Task Force Recommendation

Roger Chou, MD; Shelley Selph, MD, MPH; Tracy Dana, MLS; Christina Bougatsos, MPH; Bernadette Zakher, MBBS; Ian Blazina, MPH;

and P. Todd Korthuis, MD, MPH

Background: A 2005 U.S. Preventive Services Task Force (USPSTF)

review found good evidence that HIV screening is accurate and

that antiretroviral therapy (ART) for immunologically advanced dis-

ease is associated with substantial clinical benefits, but insufficient

evidence to determine the effects on transmission or in less immu-

nologically advanced disease.

Purpose: To update the 2005 USPSTF review on benefits and

harms of HIV screening in adolescents and adults, focusing on

research gaps identified in the prior review.

Data Sources: MEDLINE (2004 to June 2012) and the Cochrane

Library (through the second quarter of 2012).

Study Selection: Randomized trials and observational studies that

compared HIV screening strategies and reported clinical outcomes,

evaluated the effects of starting ART at different CD4 cell count

thresholds and long-term harms, or reported the effects of inter-

ventions on transmission risk.

Data Extraction: 2 authors abstracted and checked study details

and quality using predefined criteria.

Data Synthesis: No study directly evaluated the effects on clinical

outcomes of screening versus no screening for HIV infection. A

randomized trial and a subgroup analysis from a randomized trial

found that ART initiation at CD4 counts less than 0.250 ⫻10

cells/L was associated with a higher risk for death or AIDS-defining

events than initiation at CD4 counts greater than 0.350 ⫻10

cells/L (hazard ratios, 1.7 [95% CI, 1.1 to 2.5] and 5.3 [CI, 1.3 to

9.6]). Large, fair-quality cohort studies also consistently found that

ART initiation at CD4 counts of 0.350 to 0.500 ⫻10

cells/L was

associated with lower risk for death or AIDS-defining events than

delayed initiation. New evidence from good-quality cohorts with

longer-term follow-up confirms a previously observed small in-

creased risk for cardiovascular events associated with certain anti-

retrovirals. Strong evidence from 1 good-quality randomized trial

and 7 observational studies found that ART was associated with a

10- to 20-fold reduction in risk for sexual transmission of HIV.

Limitations: Only English-language articles were included. Obser-

vational studies were included. Studies done in resource-poor or

high-prevalence settings were included but might have limited ap-

plicability to general screening in the United States.

Conclusion: Previous studies have shown that HIV screening is

accurate, targeted screening misses a substantial proportion of

cases, and treatments are effective in patients with advanced im-

munodeficiency. New evidence indicates that ART reduces risk for

AIDS-defining events and death in persons with less advanced

immunodeficiency and reduces sexual transmission of HIV.

Primary Funding Source: Agency for Healthcare Research and

Quality.

Ann Intern Med. 2012;157:706-718. www.annals.org

For author affiliations, see end of text.

In 2008, an estimated 1.2 million persons in the United

States were living with HIV, and approximately 1 in 5

were unaware of their status (1–3). Incidence of HIV in

the United States is approximately 50 000 cases per year

(1, 4), with an estimated 20 000 such cases believed to be

due to transmission from persons who are unaware that

they are infected (5, 6). Screening for HIV antibodies can

detect infection in asymptomatic patients, who might ben-

eﬁt from interventions to reduce risk for AIDS-related clin-

ical events and transmission.

In 2005, the U.S. Preventive Services Task Force

(USPSTF) recommended screening all adolescents and

adults at increased risk (deﬁned as persons who reported

HIV risk factors or were evaluated in settings with an HIV

infection prevalence ⬎1%) (7) on the basis of an earlier

evidence review (8–10) that found a high yield from

screening these patients, good evidence that HIV screening

tests are accurate (sensitivity and speciﬁcity each ⬎99%),

and good evidence that treating HIV infection at immu-

nologically advanced stages of disease (deﬁned as CD4

counts ⬍0.200 ⫻10

cells/L) with antiretroviral therapy

(ART) markedly reduces risk for AIDS-related clinical

events and death. Although the USPSTF found that ART

was associated with short-term adverse events and an in-

creased risk for long-term cardiovascular events, it deter-

mined that beneﬁts substantially outweighed harms.

The USPSTF made no recommendation for or against

screening for HIV in adolescents and adults who were not

at increased risk for HIV infection (7). Because of the

lower prevalence of HIV infection in such persons, it de-

termined that the beneﬁts of screening would be smaller

than in higher-risk populations. The USPSTF found insuf-

ﬁcient evidence to estimate beneﬁts from screening persons

at less immunologically advanced stages of disease (CD4

See also:

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counts ⬎0.200 ⫻10

cells/L) or on the effects of screen-

ing and subsequent interventions on HIV transmission.

In 2006, the Centers for Disease Control and Preven-

tion (CDC) issued its revised guideline (11) recommend-

ing routine voluntary HIV screening of all persons aged 13

to 64 years, unless the prevalence of undiagnosed HIV

infection was less than 0.1%. A key reason for this recom-

mendation was evidence showing that 20% to 26% of pa-

tients with HIV infection report no risk factors (12), sug-

gesting that risk-based screening strategies miss an

important proportion of infected persons. Other reasons

for the differences between recommendations include that

the CDC placed greater weight on studies showing reduc-

tions in self-reported risky behaviors after HIV diagnosis,

accepted modeling studies to estimate effects of HIV diag-

nosis on transmission risk, and placed greater weight on

modeling studies that showed acceptable incremental cost-

effectiveness ratios for screening versus no screening in

low-prevalence populations (7).

This report updates the previous USPSTF review on

HIV screening in nonpregnant adolescents and adults. It

focuses on key research gaps identiﬁed in the earlier review

with the potential greatest effect on assessment of beneﬁts

and harms associated with screening in persons not known

to be at higher risk, including effects of screening, coun-

seling, and ART use on HIV transmission risk; effective-

ness of ART for HIV-infected persons with CD4 counts

greater than 0.200 ⫻10

cells/L, and long-term harms of

ART. The full report (13) provides detailed methods and

data for the review, including search strategies and evi-

dence tables with quality ratings of individual studies. Ad-

ditional key questions about various screening strategies,

the effects of knowledge of HIV-positive status and use of

ART on risky behaviors, and associations between viremia

or risky behaviors and HIV transmission are reviewed in

the full report (13) but are not presented here.

METHODS

Scope of the Review

We followed a standardized protocol and developed an

analytic framework (Figure) that included the following

key questions:

What are the beneﬁts of universal or targeted HIV

screening versus no screening in asymptomatic, nonpreg-

nant adolescents and adults on disease transmission, mor-

bidity, mortality, and quality of life?

What is the yield (number of new diagnoses) of HIV

screening at different intervals in nonpregnant adolescents

and adults?

How effective is ART for reducing transmission of

HIV in nonpregnant adolescents and adults with chronic

HIV infection?

How effective is behavioral counseling for reducing

transmission of HIV in nonpregnant adolescents and

adults with chronic HIV infection?

In asymptomatic, nonpregnant adolescents and adults

with chronic HIV infection, what are the effects of initiat-

ing ART at different CD4 cell count or viral load thresh-

olds on morbidity, mortality, and quality of life?

What are the longer-term harms associated with ART

for nonpregnant adolescents and adults with chronic HIV

infection?

We deﬁned “universal” testing to mean routine testing

of all persons aged 13 to 64 years, unless the prevalence of

HIV infection has been documented to be less than 0.1%

(11) and “targeted” screening to mean routine screening of

persons who have risk factors or are in high-prevalence

(⬎1%) settings (7).

Data Sources and Searches

We searched Ovid MEDLINE from 2004 to June

2012 and the Cochrane Library through the second quar-

ter of 2012 and reviewed reference lists to identify relevant

articles published in English.

Study Selection

At least 2 reviewers independently evaluated each

study to determine inclusion eligibility. Papers were se-

lected for full review if they were about HIV screening or

treatments in nonpregnant adolescents and adults, were

relevant to a key question, and met the predeﬁned inclu-

sion criteria (Appendix Table 1, available at www.annals

.org). For treatment interventions, we focused on ART and

counseling to reduce transmission risk. Outcomes were

mortality, AIDS-related events, HIV transmission risk, and

long-term (deﬁned as ⱖ2 years after initiation of treat-

ment) cardiovascular harms associated with ART. We in-

cluded randomized, controlled trials and cohort studies for

all key questions. We also included systematic reviews pub-

lished since 2010 that met all predeﬁned quality criteria

(14).

Data Abstraction and Quality Rating

One investigator abstracted details about the study de-

sign, patient population, setting, screening method, inter-

ventions, analysis, follow-up, and results. A second inves-

tigator reviewed data abstraction for accuracy. Two

investigators independently applied criteria developed by

the USPSTF (15) to rate the quality of each study as good,

fair, or poor. Discrepancies were resolved by consensus.

Data Synthesis

We assessed the aggregate internal validity (quality) of

the body of evidence for each key question as good, fair, or

poor by using methods developed by the USPSTF, on the

basis of the number, quality, and size of studies; consis-

tency of results among studies; and directness of evidence

(15). Meta-analysis was not attempted, although we re-

ported meta-analyses from published systematic reviews

that met our quality criteria.

Role of the Funding Source

This research was funded by the Agency for Health-

care Research and Quality (AHRQ) under a contract to

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support the work of the USPSTF. Investigators worked

with USPSTF members and AHRQ staff to develop and

reﬁne the scope, analytic framework, and key questions;

resolve issues arising during the project; and ﬁnalize the

report. The AHRQ had no role in study selection, quality

assessment, synthesis, or development of conclusions. The

AHRQ provided project oversight; reviewed the draft re-

port; and distributed the draft for peer review, including to

representatives of professional societies and federal agen-

cies. The AHRQ performed a ﬁnal review of the manu-

script to ensure that the analysis met methodological stan-

dards. The investigators are solely responsible for the

content and the decision to submit the manuscript for

publication.

RESULTS

The Appendix Figure (available at www.annals.org)

shows the results of the search and study selection process.

Clinical Benefits of Universal or Targeted Screening

No randomized trial or observational study compared

clinical outcomes between adults and adolescents screened

and not screened for HIV infection.

Yield of HIV Screening at Different Intervals

No randomized trial or observational study evaluated

the yield of repeated HIV screening compared with 1-time

screening or compared the yield of different strategies for

repeated screening (such as risk-based repeated screening

vs. a routinely repeated test).

Figure. Analytic framework and key questions for screening for HIV in nonpregnant adolescents and adults.

Screening

Viral load, CD4 cell

count testing

HIV Ab testingRisk factor assessment

Interventions

Asymptomatic

adolescents and

adults* (excluding

pregnant women,

dialysis patients,

transplant patients)

Key Questions:

1. What are the benefits of universal or targeted HIV screening versus no screening in asymptomatic, nonpregnant adolescents and adults on disease

transmission, morbidity, mortality, and quality of life?

2a. What is the yield (number of new diagnoses) of HIV screening at different intervals in nonpregnant adolescents and adults?

*2b. What are the effects of universal versus targeted HIV screening on testing acceptability and uptake in nonpregnant adolescents and adults?

*2c. What is the effect or opt-out versus opt-in testing or different pre- or posttest HIV counseling methods on screening uptake or rates of follow-up and

linkage to care in nonpregnant adolescents and adults?

*2d. What are the adverse effects (including false-positive results and anxiety) of rapid versus standard HIV testing in nonpregnant adolescents and adults not

known to be at higher risk?

*2e. What are the effects of universal versus targeted HIV screening on CD4 cell counts at the time of diagnosis?

*2f. What are the effects of universal versus targeted HIV screening on rates of follow-up and linkage to care in nonpregnant adolescents and adults who

screen positive?

*3a. To what extent does knowledge of HIV-positive status affect behaviors associated with increased risk for HIV transmission in nonpregnant adolescent and

adults?

*3b. To what extent does use of antiretroviral therapy affect behaviors associated with increased risk for HIV transmission in nonpregnant adolescents and

adults?

4a. How effective is antiretroviral therapy for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?

4b. How effective is behavioral counseling for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?

4c. In asymptomatic, nonpregnant adolescents and adults with chronic HIV infection, what are the effects of initiating antiretroviral therapy at different CD4

cell count or viral load thresholds on morbidity, mortality, and quality of life?

5. What are the longer-term harms associated with antiretroviral therapy for nonpregnant adolescents and adults with chronic HIV infection?

*6a. To what extent are improvements in viremia associated with reductions in HIV transmission rates in nonpregnant adolescents and adults?

*6b. To what extent are improvements in risky behaviors associated with reductions in HIV transmission rates in nonpregnant adolescents and adults?

Low CD4 cell

count or high

viral load

High CD4 cell

count and low

viral load

HIV Ab–

positive

Harms

HIV Ab–

negative

Low risk

High risk

Improved CD4

cell counts,

viremia, and

risky behaviors

Reduced

premature

death and

disability or

spread of

disease

Harms Harms

2b, 2c 2f, 2c

3a, 3b 6a, 6b

4a, 4b, 4c

HIV Ab ⫽HIV antibody.

* Selected key questions have been omitted from this article. Details on these key questions are available in the full report (13).

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Effectiveness of ART for Reducing HIV Transmission

A good-quality systematic review (16) evaluated the

association between use of ART and risk for HIV trans-

mission from HIV-positive persons to uninfected sexual

partners. It included 1 good-quality randomized, con-

trolled trial (17) and 7 observational studies (18–24) (Ap-

pendix Table 2, available at www.annals.org).

The randomized, controlled trial (HIV Prevention

Trials Network study 052) compared early ART initiation

(started at enrollment) with delayed therapy (after CD4

count decreased to ⬍0.250 ⫻10

cells/L or onset of

symptoms) in HIV-infected patients with baseline CD4

counts of 0.350 to 0.550 ⫻10

cells/L and an HIV-

negative partner (17). Fifty-four percent of the 1763 cou-

ples were from Africa, with the remainder from Brazil,

India, Thailand, and the United States. Ninety-seven per-

cent of couples were heterosexual, and 94% were married.

All couples received condoms and counseling. The trial was

designed to follow patients for 5 years but was terminated

early after meeting prespeciﬁed criteria for efﬁcacy in in-

terim analyses. At a median follow-up of 1.7 years, risk for

seroconversion in HIV-negative partners was much lower

in the early-therapy group than in the delayed-therapy

group (0.3 vs. 2.2 per 100 person-years; hazard ratio [HR],

0.11 [95% CI, 0.04 to 0.32]). When restricted to cases

that were genomically linked to the HIV-infected patient

enrolled in the trial, the HR was 0.04 (CI, 0.01 to 0.27).

Results of the 7 observational studies (18–24) in-

cluded in the systematic review (16) were consistent with

the randomized trial (17). Sample sizes ranged from 93 to

3408 couples, with typical follow-up between 1 and 3 years

(range, 3 months to 9 years). All were cohort studies of

HIV-serodiscordant, heterosexual couples from Africa, It-

aly, Spain, Brazil, or China. Six studies (18–22, 24) were

rated fair-quality and the seventh (23) was a conference

abstract. Three studies (19, 21, 24) adjusted for possible

confounding variables, such as age, sex, condom use, or

frequency of sexual intercourse.

Six (18–23) of the 7 observational studies reported

that persons receiving ART had a lower risk for HIV trans-

mission than untreated persons, for a pooled HR of 0.34

(CI, 0.13 to 0.92; I

⫽73%) (16). Exclusion of 1 study

with inadequate person-time data (24) and 1 older study

that included persons treated with monotherapy (21) re-

sulted in a pooled HR of 0.16 (CI, 0.07 to 0.35) and

eliminated statistical heterogeneity (I

⫽0%). The treat-

ment effect was also more pronounced when the analysis

was restricted to couples in which the HIV-infected person

had a CD4 count less than 0.200 ⫻10

cells/L (pooled

HR, 0.06 [CI, 0.01 to 0.54]) (18–20, 22).

Effectiveness of Behavioral Counseling for Reducing

Transmission

The previous USPSTF review (8–10) found no ran-

domized trials or controlled observational studies on the

effects of counseling HIV-positive persons about risky be-

haviors on HIV transmission risk.

There remains little direct evidence on the effects of

testing and counseling about risky behaviors on HIV trans-

mission. Two studies on effects of counseling regarding

sexual behaviors in HIV serodiscordant couples (25, 26)

were not designed to assess effects on transmission rates

and were severely underpowered (5 new HIV diagnoses

were observed in each study). No study estimated the ef-

fects of counseling HIV-positive persons about injection

drug use behaviors on transmission rates.

Effectiveness of Initiating ART at Different CD4 Cell

Count Thresholds on Clinical Outcomes

The previous USPSTF review included good-quality

randomized, controlled trials (27–29) and observational

studies (30–37) that consistently found a lower risk for

AIDS events and death with ART than with placebo or

less-intensive regimens in patients with CD4 counts less

than 0.200 ⫻10

cells/L. Evidence showing beneﬁts of

starting ART at higher CD4 cell counts was limited. Al-

though a Swiss cohort study (38) found that starting ART

at CD4 counts greater than 0.350 ⫻10

cells/L was asso-

ciated with a lower risk for death and progression to AIDS

than starting at less than 0.350 ⫻10

cells/L, 3 U.S. co-

hort studies (35–37) found no difference in risk between

starting ART at CD4 counts between 0.350 and

0.500 ⫻10

cells/L versus delaying until CD4 counts were

between 0.200 and 0.350 ⫻10

cells/L.

Two good-quality randomized trials (17, 39) pub-

lished since the previous USPSTF review and 1 subgroup

analysis (40) from another randomized trial evaluated the

effects of initiating ART at different CD4 cell count

thresholds (Table 1). Five observational studies (reported

in 7 publications) (41–45, 48, 49), each of which com-

bined data from 12 to 23 U.S., European, and Australian

cohorts (ranging from 9000 to ⬎60 000 participants and

2- to 5-year follow-up, with substantial overlap in the co-

horts included in the studies), also evaluated the effects of

starting ART at different CD4 cell count thresholds (Table

1). All of the observational studies were rated fair-quality.

None reported blinding of outcome assessors or persons

analyzing data, and attrition rates were often not reported

or were unclear. Although all studies adjusted for con-

founders, most provided insufﬁcient information to deter-

mine baseline comparability of patients starting or not

starting ART at different CD4 cell count strata.

A retrospective subgroup analysis of 477 patients in

the SMART (Strategies for Management of Antiretroviral

Therapy) randomized trial who were treatment-naive or

had stopped therapy for at least 6 months found that ART

initiation at CD4 counts less than 0.250 ⫻10

cells/L was

associated with a higher risk for death or AIDS events than

initiation at counts greater than 0.350 ⫻10

cells/L after a

mean of 18 months (HR, 5.3 [CI, 1.3 to 9.6]) (40). The

SMART trial was done in 33 primarily non–resource-poor

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Table 1. Initiating HAART at Different CD4 Cell Counts or Viral Load Thresholds on Progression to AIDS or Mortality

Study, Year (Reference) Study Name Patients,

Duration of

Follow-up

Comparison Groups

RCTs

Cohen et al, 2011 (17) HPTN 052 1763 Median,

1.7 y

Delayed treatment (n⫽877): Initiation of ART after 2

consecutive CD4 counts ⬍0.250 ⫻10

cells/L or at

onset of AIDS-related illness

Early treatment (n⫽886): Initiation of ART at CD4

count of 0.350 to 0.550 ⫻10

cells/L

Severe et al, 2010 (39) NA 816 21 mo Standard treatment (n⫽408): Same intervention as early

treatment group, started at CD4 count ⱕ0.200 ⫻

cells/L

Early treatment (n⫽408): CD4 count, 0.201 to 0.350 ⫻

cells/L; lamivudine, 150 mg, plus zidovudine,

300 mg, twice a day and efavirenz,

600 mg/d

Emery et al, 2008 (40),

and El-Sadr et al,

2006 (47)

SMART Study Group 477 (249 ART-naive) 18 mo Intermittent ART, drug conservation group: CD4 count

⬍0.250 ⫻10

cells/L, CD4 percentage ⬍15%, or

symptomatic; 131 ART-naive patients

Continuous ART, viral suppression group: CD4 count

⬎0.350 ⫻10

cells/L; 118 ART-naive patients

Cohort studies

Cain et al, 2011 (42),

and Ray et al,

2010 (43)

HIV-CAUSAL

Collaboration

20 971 (12 cohorts);

restricted to

patients with

CD4 counts

⬎0.500 ⫻10

cells/L at baseline

Mean, 1 y By CD4 count*:

0.200 ⫻10

cells/L (n⫽8066)

0.250 ⫻10

cells/L (n⫽8078)

0.300 ⫻10

cells/L (n⫽8101)

0.350 ⫻10

cells/L (n⫽8144)

0.400 ⫻10

cells/L (n⫽8201)

0.450 ⫻10

cells/L (n⫽8281)

0.500 ⫻10

cells/L (n⫽8392)

Ray et al, 2010 (43) HIV-CAUSAL

Collaboration

62 760 (12 cohorts) Mean, 3 y By CD4 count:

⬍0.100 ⫻10

cells/L (n⫽5319)

0.100 to ⬍0.200 ⫻10

cells/L (n⫽6521)

0.200 to ⬍0.350 ⫻10

cells/L (n⫽14 886)

0.350 to ⬍0.500 ⫻10

cells/L (n⫽15 360)

ⱕ0.500 ⫻10

cells/L (n⫽20 674)

Kitahata et al,

2009 (44)

NA-ACCORD 17 517 (22 cohorts) Mean, 3 y CD4 count 0.351 to 0.500 ⫻10

cells/L: early therapy

(n⫽2084) and deferred therapy

(n⫽6278)

CD4 count ⬎0.500 ⫻10

cells/L: early therapy

(n⫽2220) and deferred therapy (n⫽6936)

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Table 1—Continued

Mortality Progression to AIDS/AIDS-Related Events Mortality or Progression to

AIDS/AIDS-Related Events

Delayed vs. early treatment: 13/877 (1.5%) vs. 10/886

(1.2%); HR, 1.3 (95% CI, 0.6 to 3.0)

Extrapulmonary tuberculosis, delayed vs.

early treatment: 17/877 (2%) vs. 3/886

(0.3%); RR, 5.6 (95% CI, 1.7 to 20.0)

Pulmonary tuberculosis, delayed vs. early

treatment: 15/877 (1.7%) vs. 13/886

(1.5%); RR, 1.2 (95% CI, 0.6 to 2.4)

Delayed vs. early treatment: 65/877 (7.4%) vs. 40/886

(4.5%); HR, 1.7 (95% CI, 1.1 to 2.5)

Standard vs. early treatment: 23/408 (6%) vs. 6/408

(2%); unadjusted HR, 4.0 (95% CI, 1.6 to 9.8)

Tuberculosis, standard vs. early treatment:

36/408 (9%) vs. 18/408 (4%);

unadjusted HR, 2.0 (95% CI, 1.2 to

3.6)

Not reported

Not reported Drug conservation vs. continuous ART

(fatal and nonfatal AIDS events): 3/131

(2/100 PYs) vs. 1/118 (0.5/100 PYs);

HR, 4.1; P⫽0.22

Drug conservation vs. continuous ART: 4/131 (2.7/100

PYs) vs. 1/118 (0.5/100 PYs); HR, 5.3 (95% CI, 1.3

to 9.6)

ART initiation at CD4 count 0.500 ⫻10

cells/L (n⫽

65/8392) vs. initiation at:

0.200 ⫻10

cells/L (n⫽99/8066): HR, 0.83 (95% CI,

0.68 to 1.03)

0.250 ⫻10

cells/L (n⫽95/8078): HR, 0.92 (95% CI,

0.78 to 1.09)

0.300 ⫻10

cells/L (n⫽97/8101): HR, 0.99 (95% CI,

0.84 to 1.18)

0.350 ⫻10

cells/L (n⫽94/8144): HR, 0.99 (95% CI,

0.82 to 1.19)

0.400 ⫻10

cells/L (n⫽89/8201): HR, 0.95 (95% CI,

0.79 to 1.16)

0.450 ⫻10

cells/L (n⫽81/8281): HR, 0.97 (95% CI,

0.88 to 1.09)

ART initiation at CD4 count 0.350 ⫻10

cells/L (n⫽

94/8144) vs. initiation at:

0.200 ⫻10

cells/L (n⫽99/8066): HR, 0.85 (95% CI,

0.68 to 1.05)

0.250 ⫻10

cells/L (n⫽95/8078): HR, 0.93 (95% CI,

0.75 to 1.16)

0.300 ⫻10

cells/L (n⫽97/8101): HR, 1.01 (95% CI,

0.79 to 1.28)

0.400 ⫻10

cells/L (n⫽89/8201): HR, 0.97 (95% CI,

0.85 to 1.10)

0.450 ⫻10

cells/L (n⫽81/8281): HR, 0.99 (95% CI,

0.79 to 1.22)

0.500 ⫻10

cells/L (n⫽65/8392): HR, 1.01 (95% CI,

0.74 to 1.41)

Not reported ART initiation at CD4 count 0.500 ⫻10

cells/L

(n⫽158/8392) vs. initiation at:

0.200 ⫻10

cells/L (n⫽330/8066): HR, 0.53 (95%

CI, 0.47 to 0.60)

0.250 ⫻10

cells/L (n⫽329/8078): HR, 0.60 (95%

CI, 0.54 to 0.67)

0.300 ⫻10

cells/L (n⫽317/8101): HR, 0.68 (95%

CI, 0.61 to 0.75)

0.350 ⫻10

cells/L (n⫽296/8144): HR, 0.72 (95%

CI, 0.64 to 0.81)

0.400 ⫻10

cells/L (n⫽256/8201): HR, 0.78 (95%

CI, 0.68 to 0.87)

0.450 ⫻10

cells/L (n⫽209/8281): HR, 0.88 (95%

CI, 0.82 to 0.93)

ART initiation at CD4 count 0.350 ⫻10

cells/L

(n⫽296/8144) vs. initiation at:

0.200 ⫻10

cells/L (n⫽330/8066): HR, 0.73 (95%

CI, 0.64 to 0.83)

0.250 ⫻10

cells/L (n⫽329/8078): HR, 0.83 (95%

CI, 0.72 to 0.95)

0.300 ⫻10

cells/L (n⫽317/8101): HR, 0.93 (95%

CI, 0.81 to 1.09)

0.400 ⫻10

cells/L (n⫽256/8201): HR, 1.06 (95%

CI, 0.99 to 1.16)

0.450 ⫻10

cells/L (n⫽209/8281): HR, 1.20 (95%

CI, 1.05 to 1.39)

0.500 ⫻10

cells/L (n⫽158/8392): HR, 1.39 (95%

CI, 1.14 to 1.69)

Initiation vs. no initiation of ART, by CD4 count:

⬍0.100 ⫻10

cells/L: HR, 0.29 (95% CI, 0.22 to 0.37)

0.100 to ⬍0.200 ⫻10

cells/L: HR, 0.33 (95% CI,

0.25 to 0.44)

0.200 to ⬍0.350 ⫻10

cells/L: HR, 0.38 (95% CI,

0.28 to 0.52)

0.350 to ⬍0.500 ⫻10

cells/L: HR, 0.55 (95% CI,

0.41 to 0.74)

ⱕ0.500 ⫻10

cells/L: HR, 0.77 (95% CI, 0.58 to 1.01)

Not reported Not reported

ART initiation at CD4 count 0.351 to 0.500 vs. ⱕ0.350 ⫻

cells/L: adjusted RR, 0.61 (95% CI, 0.46 to 0.83)

ART initiation at CD4 count ⬎0.500 vs. ⱕ0.500 ⫻10

cells/L: adjusted RR, 0.54 (95% CI, 0.35 to 0.83)

Not reported Not reported

Continued on following page

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countries. The HIV Prevention Trials Network study 052,

conducted in 1763 patients from primarily resource-poor

countries, also found initiation at CD4 counts less than

0.250 ⫻10

cells/L associated with a higher risk for death

or AIDS events than initiation at counts greater than

0.350 ⫻10

cells/L after a median of 1.7 years (HR, 1.7

[CI, 1.1 to 2.5]) (17). Another randomized trial (39) with

816 participants found that ART initiation at CD4 counts

less than 0.200 ⫻10

cells/L was associated with higher

mortality than initiation at 0.201 to 0.350 ⫻10

cells/L

(HR, 4.0 [CI, 1.6 to 9.8]; P⫽0.001), but this trial was

conducted in Haiti and evaluated lower CD4 count cutoffs

for treatment than those in the United States.

Four observational studies (42–45, 48) consistently

found that ART initiation at CD4 counts between 0.350

and 0.500 ⫻10

cells/L was associated with a lower risk

for death than deferred or no ART. One other study (49)

found a reduction in risk that was not statistically signiﬁ-

cant. The HIV-CAUSAL (HIV Cohorts Analyzed Using

Structural Approaches to Longitudinal data) collaboration

(43), the largest study in our review (62 760 participants

from 12 cohorts), found that ART initiation at CD4

counts of 0.350 to 0.500 ⫻10

cells/L was associated with

a lower risk for death than noninitiation at these counts

after 3.3 years of follow-up (adjusted HR, 0.55 [CI, 0.41

to 0.74]). Similarly, the NA-ACCORD (North American

AIDS Cohort Collaboration on Research and Design)

(44), with 17 517 participants from 22 cohorts, found that

ART initiation at CD4 counts of 0.351 to 0.500 ⫻10

cells/L was associated with a lower risk for death than de-

ferred treatment at these CD4 cell counts after 3 years of

follow-up (adjusted RR, 0.61 [CI, 0.46 to 0.83]). In 2

studies (45, 49), ART initiation at CD4 counts greater

than 0.350 ⫻10

cells/L was also associated with a lower

risk for the combined outcome of AIDS-deﬁning events

and death than deferred or no ART initiation. One other

study (48) found a reduction in risk that was not statisti-

cally signiﬁcant.

Studies on ART initiation at CD4 counts greater than

0.500 ⫻10

cells/L were less consistent. The NA-

ACCORD cohort study (44) found that ART initiation at

CD4 counts greater than 0.500 ⫻10

cells/L was associ-

ated with lower mortality than deferred therapy (adjusted

RR, 0.54 [CI, 0.35 to 0.83]) and the HIV-CAUSAL col-

Table 1—Continued

Study, Year (Reference) Study Name Patients,

Duration of

Follow-up

Comparison Groups

May et al, 2007 (45);

Lanoy et al,

2009 (41); and

Moore et al,

2009 (46)

ART Cohort

Collaboration

20 379 (12 cohorts) Mean, 3 y By CD4 count:

⬍0.025 ⫻10

cells/L (n⫽2034)

0.025 to 0.049 ⫻10

cells/L (n⫽1295)

0.050 to 0.099 ⫻10

cells/L (n⫽2059)

0.100 to 0.199 ⫻10

cells/L (n⫽3782)

0.200 to 0.349 ⫻10

cells/L (n⫽5550)

ⱕ0.350 ⫻10

cells/L (n⫽5659)

Sterne et al, 2009 (49) When to Start

Consortium

45 691 (18 cohorts);

24 444 received

HAART

Mean, 3 y By CD4 count:

⬍0.051 ⫻10

cells/L (n⫽2594)

0.051 to 0.150 ⫻10

cells/L (n⫽4638)

0.151 to 0.250 ⫻10

cells/L (n⫽6406)

0.251 to 0.350 ⫻10

cells/L (n⫽5753)

0.351 to 0.400 ⫻10

cells/L (n⫽3260)

0.451 to 0.500 ⫻10

cells/L (n⫽1793)

Writing Committee for

the CASCADE

Collaboration,

2011 (48)

NA 9455 (23 cohorts) Median, 5 y Unique individuals (numbers overlap):

0 to 0.049 ⫻10

cells/L (n⫽183)

0.050 to 0.199 ⫻10

cells/L (n⫽1521)

0.200 to 0.349 ⫻10

cells/L (n⫽4459)

0.350 to 0.499 ⫻10

cells/L (n⫽5527)

0.500 to 0.799 ⫻10

cells/L (n⫽5162)

ART ⫽antiretroviral therapy; CASCADE ⫽Concerted Action on Seroconversion to AIDS and Death in Europe; HAART ⫽highly active antiretroviral therapy;

HIV-CAUSAL ⫽HIV Cohorts Analyzed Using Structural Approaches to Longitudinal data; HPTN ⫽HIV Prevention Trials Network; HR ⫽hazard ratio; NA ⫽not

applicable; NA-ACCORD ⫽North American AIDS Cohort Collaboration on Research and Design; PY ⫽person-year; RCT ⫽randomized, controlled trial; RD ⫽risk

difference; RR ⫽relative risk; SMART ⫽Strategies for Management of Antiretroviral Therapy.

*Patient-level data may cross CD4 cell count thresholds.

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laboration (43) found a lower mortality risk that was not

statistically signiﬁcant (adjusted HR, 0.77 [CI, 0.58 to

1.0]). Another analysis from the HIV-CAUSAL Collabo-

ration (42) that directly compared ART initiation at CD4

counts greater than 0.500 ⫻10

cells/L with initiation at

greater than 0.350 ⫻10

cells/L found no difference in

mortality (HR, 0.99 [CI, 0.89 to 1.2]). Two other large

cohort studies found that ART initiation at CD4 counts

greater than 0.500 ⫻10

cells/L was associated with no

difference in risk for death when compared with noninitia-

tion (48) or slightly delayed initiation (49). In all 4 studies,

absolute mortality rates were low (2% to 5%) in patients

with CD4 counts greater than 0.500 ⫻10

cells/L.

Results were also mixed for the combined outcome of

death plus AIDS-deﬁning events (not reported in the NA-

ACCORD study [44]). The HIV-CAUSAL collaboration

(42) found that ART initiation at CD4 counts greater than

0.500 ⫻10

cells/L was associated with a lower risk for

AIDS-deﬁning events or death than initiation at greater

than 0.350 ⫻10

cells/L (HR, 0.72 [CI, 0.64 to 0.81]).

Two other studies (48, 49) found no clear association be-

tween starting or not starting ART at CD4 counts greater

than 0.500 ⫻10

cells/L and risk for AIDS-deﬁning

events or death.

Longer-Term Harms Associated With ART

The 2005 USPSTF review included results from the

large, ongoing DAD (Data Collection on Adverse Events

of Anti-HIV Drugs) study (23 468 participants), which

found that increased risk for myocardial infarction was as-

sociated with longer exposure to ART (adjusted RR, 1.3

per year of exposure [CI, 1.1 to 1.4 per year of exposure]),

although absolute event rates were low (3.5 per 1000

person-years) (50).

Subsequent analyses from the DAD study (51–53)

and 3 other cohort studies (54–56) reported cardiovascular

harms associated with ART through 4 to 6 years of

follow-up (Appendix Table 3, available at www.annals

.org). Sample sizes ranged from 2952 to more than 30 000

persons. All of the studies were rated good-quality except 1,

which was rated fair-quality because of lack of detail about

baseline patient characteristics and blinding of study personnel

(54). All studies adjusted for multiple confounders.

Like the earlier DAD results, the most recent analysis

found that longer exposure to indinavir alone (adjusted

RR, 1.1 per year of exposure [CI, 1.1 to 1.2 per year of

exposure]), ritonavir-boosted indinavir (adjusted RR, 1.2

per year of exposure [CI, 1.1 to 1.3 per year of exposure]),

and ritonavir-boosted lopinavir (adjusted RR, 1.1 per year

Table 1—Continued

Mortality Progression to AIDS/AIDS-Related Events Mortality or Progression to

AIDS/AIDS-Related Events

ART initiation at varying CD4 cell counts vs. initiation at

⬍0.025 ⫻10

cells/L:

0.025 to 0.049 ⫻10

cells/L: 111/1295 vs. 222/2034;

HR, 0.82 (95% CI, 0.66 to 1.04)

0.050 to 0.099 ⫻10

cells/L: 162/2059 vs. 222/2034;

HR, 0.77 (95% CI, 0.63 to 0.95)

0.100 to 0.199 ⫻10

cells/L: 202/3782 vs. 222/2034;

HR, 0.67 (95% CI, 0.55 to 0.82)

0.200 to 0.349 ⫻10

cells/L: 178/5550 vs. 222/2034;

HR, 0.48 (95% CI, 0.39 to 0.60)

ⱕ0.350 ⫻10

cells/L: 130/5659 vs. 222/2034; HR,

0.34 (95% CI, 0.27 to 0.44)

Not reported ART initiation at varying CD4 cell counts vs. initiation at

⬍0.025 ⫻10

cells/L:

0.025 to 0.049 ⫻10

cells/L: 277/1295 vs.

519/2034; HR, 0.85 (95% CI, 0.73 to 0.98)

0.050 to 0.099 ⫻10

cells/L: 408/2059 vs.

519/2034; HR, 0.76 (95% CI, 0.66 to 0.87)

0.100 to 0.199 ⫻10

cells/L: 445/3782 vs.

519/2034; HR, 0.49 (95% CI, 0.43 to 0.56)

0.200 to 0.349 ⫻10

cells/L: 361/5550 vs.

519/2034; HR, 0.29 (95% CI, 0.25 to 0.33)

ⱕ0.350 ⫻10

cells/L: 298/5659 vs. 519/2034;

HR, 0.23 (95% CI, 0.19 to 0.27)

ART initiation at varying CD4 cell counts vs. initiation at

0.351 to 0.400 ⫻10

cells/L:

0.451 to 0.550 ⫻10

cells/L: HR, 0.93 (95% CI, 0.6

to 1.4)

0.251 to 0.350 ⫻10

cells/L: HR, 0.83 (95% CI, 0.59

to 1.25)

0.151 to 0.250 ⫻10

cells/L: HR, 0.67 (95% CI, 0.51

to 0.99)

0.051 to 0.150 ⫻10

cells/L: HR, 0.47 (95% CI, 0.34

to 0.58)

Not reported ART initiation at varying CD4 cell counts vs. initiation at

0.351 to 0.450 ⫻10

cells/L:

0.251 to 0.350 ⫻10

cells/L: HR, 0.74 (95% CI, 0.59

to 0.95)

0.151 to 0.250 ⫻10

cells/L: HR, 0.45 (95% CI, 0.37

to 0.53)

0.051 to 0.150 ⫻10

cells/L: HR, 0.18 (95% CI, 0.15

to 0.21)

Initiation vs. no initiation of ART during the index month,

by CD4 count:

0 to 0.049 ⫻10

cells/L: HR, 0.37 (95% CI, 0.14 to

0.95); RD, ⫺18.2 (95% CI, ⫺32 to ⫺4.4)

0.050 to 0.199 ⫻10

cells/L: HR, 0.55 (95% CI, 0.28

to 1.07); RD, ⫺7.2 (95% CI, ⫺10.1 to ⫺4.4)

0.200 to 0.349 ⫻10

cells/L: HR, 0.71 (95% CI, 0.44

to 1.15); RD, ⫺1.4 (95% CI, ⫺3.0 to 0.3)

0.350 to 0.499 ⫻10

cells/L: HR, 0.51 (95% CI, 0.33

to 0.80); RD, ⫺1.4 (95% CI, ⫺2.2 to ⫺0.6)

0.500 to 0.799 ⫻10

cells/L: HR, 1.02 (95% CI, 0.49

to 2.12); RD, ⫺0.4 (95% CI, ⫺2 to 1.2)

Not reported Initiation vs. no initiation of ART during index month, by

CD4 count:

0 to 0.049 ⫻10

cells/L: HR, 0.32 (95% CI, 0.17 to

0.59); RD, ⫺30 (95% CI, ⫺45.1 to ⫺15)

0.050 to 0.199 ⫻10

cells/L: HR, 0.48 (95% CI, 0.31

to 0.74); RD, ⫺15 (95% CI, ⫺19.7 to ⫺10.3)

0.200 to 0.349 ⫻10

cells/L: HR, 0.59 (95% CI, 0.43

to 0.81); RD, ⫺4.8 (95% CI, ⫺7to⫺2.6)

0.350 to 0.499 ⫻10

cells/L: HR, 0.75 (95% CI, 0.49

to 1.14); RD, ⫺2.9 (95% CI, ⫺5to⫺0.9)

0.500 to 0.799 ⫻10

cells/L: HR, 1.10 (95% CI, 0.67

to 1.79); RD, 0.3 (95% CI, ⫺3.7 to 4.2)

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of exposure [CI, 1.0 to 1.2 per year of exposure]) were each

associated with a slightly higher risk for myocardial infarc-

tion than nonuse (53). No other protease inhibitor was

associated with increased myocardial risk.

Evidence on the association between the nucleoside

reverse transcriptase inhibitor abacavir and risk for myocar-

dial infarction is mixed. Although 2 studies (53, 55) found

that abacavir was associated with increased risk (adjusted

RRs, 1.7 and 2.0), 2 others (54, 56) found no association

(adjusted HRs, 0.6 and 1.2).

The DAD study also found that recent didanosine use

was associated with increased myocardial infarction risk

(adjusted RR, 1.4 [CI, 1.1 to 1.8]), but found no associa-

tion when analyses were based on cumulative didanosine

exposure (53). No association was found between use of

other nucleoside reverse transcriptase inhibitors or the non-

nucleoside reverse transcriptase inhibitors nevirapine or

efavirenz and increased risk for cardiovascular events (53).

DISCUSSION

As in the 2005 USPSTF review (8–10), we found no

direct evidence on the effects of screening for HIV infec-

tion versus no screening on clinical outcomes. Table 2

summarizes the other evidence reviewed in this update.

The 2005 review found good evidence that HIV

screening tests are accurate and that identifying undiag-

nosed HIV infection and treating immunologically ad-

vanced disease (CD4 count ⬍0.200 ⫻10

cells/L) are as-

sociated with substantial clinical beneﬁts. However, it

found insufﬁcient evidence to estimate the effects of diag-

nosis and subsequent interventions on transmission risks or

the clinical beneﬁts of ART in patients with less immuno-

logically advanced disease. New studies included in this

update (17, 39, 40, 43–45, 48, 49) provide strong evi-

dence for the effectiveness of initiating ART at CD4

counts between 0.350 and 0.500 ⫻10

cells/L, although

evidence showing beneﬁt is less consistent for ART initia-

tion at greater than 0.500 ⫻10

cells/L (43, 44, 48, 49).

Recent studies indicate that about 54% of patients present

for initial HIV care with CD4 counts less than

0.350 ⫻10

cells/L (57) and about 75% were diagnosed at

CD4 counts less than 0.500 ⫻10

cells/L (58), suggesting

that many patients identiﬁed by screening would beneﬁt

from immediate ART initiation. Additional research (51–

Table 2. Summary of Evidence

Key Question Main Findings From the 2005 USPSTF

Review

Number and Type of

Studies Identified for

Update

Overall

Quality*

What are the benefits of universal or targeted HIV screening

versus no screening in asymptomatic, nonpregnant

adolescents and adults on disease transmission, morbidity,

mortality, and quality of life?

No evidence No studies –

What is the yield (number of new diagnoses) of HIV

screening at different intervals in nonpregnant adolescents

and adults?

No evidence No studies –

How effective is ART for reducing transmission of HIV in

nonpregnant adolescents and adults with chronic HIV

infection?

No studies 1 systematic review

(1 RCT and 7

observational

studies)

Good

How effective is behavioral counseling for reducing

transmission of HIV in nonpregnant adolescents and

adults with chronic HIV infection?

No RCTs or controlled observational

studies

1 RCT and 1

before–after study

Poor

In asymptomatic, nonpregnant adolescents and adults with

chronic HIV infection, what are the effects of initiating

ART at different CD4 cell counts or viral load thresholds

on morbidity, mortality, and quality of life?

1 cohort study found that initiating ART at

CD4 counts ⬎0.350 ⫻10

cells/L was

associated with lower risk for AIDS

events and mortality than delayed

initiation, but 3 others found no

difference in risk

3 RCTs and 5 large

collaborative

cohort studies

Good

What are the longer-term harms associated with ART for

nonpregnant adolescents and adults with chronic HIV

infection?

1 large cohort study found that longer

duration of exposure to some protease

inhibitors was associated with increased

risk for myocardial infarction (RR, 1.3

per year of exposure [95% CI, 1.1 to

1.4])

4 cohort studies

(reported in 6

publications)

Good

ART ⫽antiretroviral therapy; HR ⫽hazard ratio; MI ⫽myocardial infarction; RCT ⫽randomized, controlled trial; RR ⫽relative risk; USPSTF ⫽U.S. Preventive Services

Task Force.

*Based on new evidence identiﬁed for this update plus previously reviewed evidence.

†Cost-effectiveness modeling studies are not included in this summary table.

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53, 55) conﬁrms previous ﬁndings of a small but statisti-

cally signiﬁcant increase in risk for long-term cardiovascu-

lar harms associated with use of certain protease inhibitors.

In the DAD study, the absolute increase in risk per year of

exposure with certain older protease inhibitors was about

0.3 myocardial infarctions per 1000 person-years (53),

compared with an absolute decrease in mortality of about

3.2 to 20 per 1000 person-years after initiating ART, de-

pending on the CD4 cell count at baseline (43). Whether

current ﬁrst-line protease inhibitors and other antiretrovi-

rals are also associated with increased cardiovascular risk

is not yet established. Long-term ART is also associated

with other harms, including osteoporotic fractures (59)

and lipodystrophy (60), that were not addressed in this

review.

Strong evidence from a randomized trial and multiple

observational studies (16, 17) indicates that ART use is

associated with a 10- to 20-fold reduction in risk for sexual

transmission. Recent evidence showing that counseling in-

terventions were relatively ineffective in reducing risky be-

haviors in HIV-infected persons (61) suggests that the ben-

eﬁcial effects of screening on transmission are probably

driven by use of ART.

Our study has limitations. We excluded non–English-

language articles, which could have resulted in language

bias, although we identiﬁed no non–English-language

studies that would have met our inclusion criteria. We did

not search for studies published only as abstracts and could

not formally assess for publication bias by using graphical

or statistical methods because of the few studies for each

key question and the differences in study design, popula-

tions, and outcomes assessed. We included observational

studies, which are more susceptible to bias and confound-

ing than well-conducted randomized trials, although we

focused on results from studies that performed statistical

adjustment for potential confounding. We also included

studies conducted in resource-poor and high-prevalence

settings, which could limit the applicability of our ﬁndings

to U.S. practice.

Additional research may further clarify beneﬁts and

harms of screening. Continued follow-up of patients re-

ceiving ART is needed to further understand the effects of

long-term exposure, because many patients receive treat-

ment for far longer than the 6 years evaluated in the lon-

gest studies to date. No clinical study has evaluated the

yield of repeated HIV screening, which probably depends on

the incidence of new infections in a population (61–63). The

START (Strategic Timing of Antiretroviral Treatment) ran-

domized trial (64), which compares ART initiation at CD4

counts greater than 0.500 ⫻10

cells/L with deferred treat-

ment until CD4 counts decrease to less than 0.350 ⫻10

Table 2—Continued

Limitations Consistency Applicability Summary of Findings for 2012 Update

No studies No studies No studies No study directly compared clinical outcomes between adults and

adolescents screened and not screened for HIV infection.

No studies No studies No studies No study evaluated the yield of repeated HIV screening

compared with one-time screening.†

Only 1 RCT Consistent Some studies conducted

in resource-poor

settings

An RCT found that immediate ART in persons with a baseline

CD4 count of 0.350 to 0.550 ⫻10

cells/L was associated

with substantially lower risk for transmission than delayed

therapy (HR, 0.04 [95% CI, 0.01 to 0.27]). Observational

studies were consistent with the RCT (pooled HR, 0.16 [95%

CI, 0.07 to 0.35]).

Underpowered to evaluate

effects on transmission

Could not

determine

No major issues Studies identified too few cases of new HIV infection to evaluate

effects of counseling interventions on transmission risk.

1 RCT reported a subgroup

analysis, some overlap in

patients evaluated in the

cohort studies

Some inconsistency

for CD4 cell

counts

⬎0.500 ⫻

cells/L

1 RCT evaluated CD4 cell

count thresholds not

applicable to U.S.

practice in a resource-

poor setting

An RCT and a subgroup analysis from another RCT found that

initiating ART at CD4 counts ⬍0.250 ⫻10

cells/L was

associated with higher risk for death or AIDS events than

initiation at CD4 counts ⬎0.350 ⫻10

cells/L. Five large

observational studies also found that initiating ART at CD4

counts between 0.350 and 0.500 ⫻10

cells/L was associated

with lower risk for death than deferred or no ART. Four studies

on initiation of ART at CD4 counts ⬎0.500 ⫻10

cells/L did

not consistently demonstrate clinical benefits.

No major limitations Consistent Duration of follow-up

about 6 y

Additional follow-up from a large cohort study included in the

previous USPSTF review found some protease inhibitors

associated with increased risk for MI (RR, 1.1 to 1.2 per year

of exposure). Evidence on abacavir from 4 cohort studies was

mixed, and no clear association was shown between other

antiretrovirals and increased risk for cardiovascular events.

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cells/L, is currently recruiting and should help further clarify

the effects of very early ART initiation.

The main area of discrepancy between HIV screening

guidelines is whether to routinely screen populations not

known to be at increased risk (11, 65). Screening tests for

HIV are highly accurate, but targeted screening misses a

substantial proportion of infected persons because of un-

disclosed or unknown risk factors. Evidence published

since the 2005 USPSTF review shows highly beneﬁcial

effects of ART for reducing sexual transmission of HIV

and risk for AIDS-deﬁning events and death in persons

with less immunologically advanced stages of disease.

From Oregon Evidence-based Practice Center and Oregon Health &

Science University, Portland, Oregon.

Acknowledgment: The authors thank Laurie Hoyt Huffman, MS, and

Jennifer Croswell, MD, MPH, as well as U.S. Preventive Services Task

Force leads Susan Curry, PhD; Virginia Moyer, MD, MPH; Wanda

Nicholson, MD, MPH, MBA; Timothy Wilt, MD, MPH; and Douglas

Owens, MD, MS.

Grant Support: By contract HHSA 290-2007-10057-I, task order 8,

from the Agency for Healthcare Research and Quality.

Potential Conflicts of Interest: Dr. Chou: Grant: Agency for Health-

care Research and Quality. Dr. Selph: Payment for writing or reviewing

the manuscript: Agency for Healthcare Research and Quality. Dr. Dana:

Grant (money to institution): Agency for Healthcare Research and Qual-

ity; Grants/grants pending: Agency for Healthcare Research and Quality.

Dr. Bougatsos: Other: This manuscript was based on a report funded by

the Agency for Healthcare Research and Quality. Dr. Zakher: Grant

(money to institution): Agency for Healthcare Research and Quality; Sup-

port for travel to meetings for the study or other purposes (money to institu-

tion): Agency for Healthcare Research and Quality. Dr. Blazina: Grant

(money to institution): Agency for Healthcare Research and Quality; Sup-

port for travel to meetings for the study or other purposes (money to institu-

tion): Agency for Healthcare Research and Quality. Disclosures can also

be viewed at www.acponline.org/authors/icmje/ConﬂictOfInterestForms

.do?msNum⫽M12-1193.

Requests for Single Reprints: Roger Chou, MD, Oregon Health &

Science University; 3181 Southwest Sam Jackson Park Road, Mail Code

BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current author addresses and author contributions are available at

www.annals.org.

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CME

while you keep up with medicine

annals.org/cme.aspx

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718 20 November 2012 Annals of Internal Medicine Volume 157 • Number 10 www.annals.org

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Current Author Addresses: Drs. Chou, Selph, and Korthuis; Ms. Dana;

Ms. Bougatsos; Ms. Zakher, and Mr. Blazina: 3181 Southwest Sam

Jackson Park Road, Mail Code BICC, Portland, OR 97239.

Author Contributions: Conception and design: R. Chou, P.T. Korthuis.

Analysis and interpretation of the data: R. Chou, S. Selph, T. Dana, C.

Bougatsos, B. Zakher, P.T. Korthuis.

Drafting of the article: R. Chou, S. Selph, T. Dana, C. Bougatsos, B.

Zakher, I. Blazina.

Critical revision of the article for important intellectual content: R.

Chou, T. Dana, B. Zakher, I. Blazina, P.T. Korthuis.

Final approval of the article: R. Chou, B. Zakher, I. Blazina, P.T.

Korthuis.

Statistical expertise: R. Chou.

Obtaining of funding: R. Chou.

Administrative, technical, or logistic support: R. Chou, T. Dana, C.

Bougatsos, I. Blazina.

Collection and assembly of data: R. Chou, S. Selph, T. Dana, C. Bou-

gatsos, B. Zakher, I. Blazina, P.T. Korthuis.

Annals of Internal Medicine

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Appendix Table 1. Inclusion and Exclusion Criteria, per Key Question

Key Question Include Exclude

All questions

Settings Primary care or other settings generalizable to primary care (e.g.,

family planning clinics or school-based health clinics), other health

care settings in which screening is commonly performed (e.g.,

emergency department or urgent care). Focus on studies

conducted in the United States and other developed countries,

unless studies are not available in those settings.

Developing countries, unless

fair- or good-quality trials

and studies in the United

States are lacking

What are the benefits of universal or targeted HIV screening

versus no screening in asymptomatic, nonpregnant

adolescents and adults on disease transmission, morbidity,

mortality, and quality of life?

Populations Asymptomatic adolescents and adults Known HIV infection, receiving

dialysis, posttransplant, or

occupational exposure

Interventions Rapid or standard HIV testing

Outcomes Reduction in transmission rates of HIV and morbidity and mortality

related to HIV infection and quality of life

Comparisons Universal or targeted HIV screening vs. no screening or each another

Study designs Randomized, controlled trials and controlled observational studies Uncontrolled observational

studies

What is the yield (number of new diagnoses) of HIV screening at

different intervals in nonpregnant adolescents and adults?

Populations Asymptomatic adolescents and adults Known HIV infection, receiving

dialysis, posttransplant, or

occupational exposure

Interventions Rapid or standard HIV testing

Outcomes Number of positive test results

Comparisons Repeated HIV screening vs. 1-time screening or screening at one

interval vs. another interval

Study designs Randomized, controlled trials and controlled observational studies

How effective is ART for reducing transmission of HIV in

nonpregnant adolescents and adults with chronic HIV

infection?

Populations HIV-positive adolescents and adults Acute HIV infection

Interventions Use of ART

Comparisons Use of ART vs. no ART

Outcomes Transmission rates

Study designs Randomized, controlled trials or controlled observational studies

How effective is behavioral counseling for reducing transmission

of HIV in nonpregnant adolescents and adults with chronic

HIV infection?

Populations HIV-positive adolescents and adults Acute HIV infection

Interventions Behavioral counseling interventions (pre- and posttest) to reduce

risky sexual behaviors or enhance protective sexual behaviors for

those who were asymptomatic and identified through screening

Comparisons Counseling vs. usual care

Outcomes Transmission rates

Study designs Randomized, controlled trials or controlled observational studies

In asymptomatic, nonpregnant adolescents and adults with

chronic HIV infection, what are the effects of initiating ART

at different CD4 cell count or viral load thresholds on

morbidity, mortality, and quality of life?

Populations HIV-positive adolescents and adults Acute HIV infection

Interventions Antiretroviral regimens

Comparisons Initiation of ART earlier vs. later

Outcomes Morbidity and mortality related to HIV infection and quality of life

Study designs Randomized, controlled trials or controlled observational studies

What are the longer-term harms associated with ART for

nonpregnant adolescents and adults with chronic HIV

infection?

Populations HIV-positive adolescents and adults Acute HIV infection or

receiving or previously

received HAART

Interventions Antiretroviral regimens

Outcomes Cardiovascular effects

Study designs Any

Timing Long-term follow up, defined as ⬎2y

ART ⫽antiretroviral therapy; HAART ⫽highly active antiretroviral therapy.

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Appendix Figure. Summary of evidence search and selection.

Included articles (n = 25)‡

Key question 1 (screening and clinical outcomes): 0 studies

Key question 2a (screening intervals): 0 studies

Key question 4a (ART and transmission risk): 1

systematic review (1 RCT and 7 observational studies)

Key question 4b (behavioral counseling and transmission risk): 1

RCT and 1 observational study

Key question 4c (initiation of ART at different CD4 counts):

3 RCTs and 5 large cohort studies

Key question 5 (longer-term harms of ART): 4 cohort studies

(6 publications)

Excluded (n = 820)

Wrong population: 111

Wrong intervention: 69

Wrong outcomes: 393

Wrong study design for key question: 149

No original data: 69

Inadequate duration: 25

Sample size too small: 4

Full-text articles reviewed for

relevance to key questions

(n = 876)

Abstracts of potentially relevant

articles identified in MEDLINE, the

Cochrane Library*, and other sources†

(n = 10 297)

Abstracts and background

articles excluded (n = 9421)

Pertain to key questions that have been

omitted from this article (n = 31)

ART ⫽antiretroviral therapy; RCT ⫽randomized, controlled trial.

*Includes the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.

†Includes reference lists and sources suggested by peer reviewers.

‡Some articles are included for more than 1 key question.

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Appendix Table 2. Evidence Table of Studies of Counseling or ART Use on HIV Transmission

Study, Year

(Reference)

Study Design

Details

Location Duration of

Follow-up

Treatment and

Comparison Groups

Demographic

Characteristics/Baseline

Disease

Participants Virologic Response CD4 Cell Count

Response

Outcomes Quality

Rating

RCT

Cohen et al,

2011 (17)

RCT Botswana, Kenya,

Malawi, South

Africa,

Zimbabwe,

India, Brazil,

Thailand, and

United States

Median, 42 mo Treatment: Immediate

ART

Comparison: Delayed

ART initiated after

CD4 count

decreased to

ⱕ0.250 ⫻109

cells/L or onset of

AIDS-related illness

61% of participants

between ages 26 and

40 y; median CD4

count, 0.442 ⫻109

cells/L for

early-therapy group

and 0.428 ⫻109

cells/L for

delayed-therapy

group

10 838 screened, 1763

couples enrolled

Virologic failure,

immediate vs.

delayed treatment:

5% (45/886) vs.

3% (5/184);

P⫽0.23

Treatment: 0.442 ⫻

109cells/L at

enrollment to

0.603 ⫻109

cells/L at 12 mo

Comparison: 0.428

⫻109cells/L at

enrollment to

0.399 ⫻109

cells/L at 12 mo

Immediate vs. delayed treatment:

Transmission events: 4 events

(IR, 0.3/100 PYs [95% CI, 0.1

to 0.6/100 PYs]) vs. 35 events

(IR, 2.2/100 PYs [95% CI, 1.6

to 3.1/100 PYs]; HR, 0.11

[95% CI, 0.04 to 0.32]);

P⬍0.001)

Total clinical events: HR, 0.59

(95% CI, 0.40 to 0.88)

Linked transmission: HR, 0.04

(95% CI, 0.01 to 0.28)

Good

Observational

studies

Del Romero

et al,

2010 (18)

Prospective

cohort

Spain 1355

couple-years

ART vs. no ART Men, 83% (index cases);

median age, 29 y

(women) and 32 y

(men); median CD4

count, 0.500 ⫻109

cells/L (IQR, 0.295 to

0.700 ⫻109cells/L);

median plasma HIV

RNA, 200 copies/mL

(IQR, ND to 8876

copies/mL); 54%

detectable viral load

648 eligible couples;

602 were

serodiscordant at

first visit and 424

were serodiscordant

at follow-up

Detectable viral load in

93% (111/120) not

receiving ART vs.

21% (30/145)

receiving ART;

P⬍0.001

Not reported No ART vs. ART:

Proportion engaging in

unprotected sexual intercourse:

57% (73/476) vs. 46%

(69/149); P⫽0.019

Transmission: 5 instances

(0.4/100 couple-years [95%

CI, 0.2 to 1.4/100

couple-years]) vs. 0 instances

(0/100 couple-years [95% CI,

0 to 1.1/100 couple-years])

Fair

Donnell

et al,

2010 (19)

Pre–post

analysis of

prospective

cohort

data

14 sites in 7

African

countries

(Botswana,

Kenya,

Rwanda,

South Africa,

Tanzania,

Uganda, and

Zambia)

Median at ART

initiation,

13 mo

Pre-ART vs. post-ART

transmission

HIV-infected partner vs.

HIV-susceptible

partner: mean age, 32

vs. 33 y; women,

68% vs. 32%;

HSV-2–positive,

100% vs. 68%

3408 enrolled, 3381

analyzed

Note: 27 couples’

baseline serology did

not confirm HIV-1

and HSV-2

Not reported Not reported Pre- vs. post-ART transmission:

Overall: 102/4558 PYs (IR,

2.24 [95% CI, 1.84 to 2.72])

vs. 1/273 PYs (IR, 0.37 [95%

CI, 0.09 to 2.04])

Overall adjusted incidence rate

ratio: 0.08 (95% CI, 0.00 to

0.57)

Good

Melo et al,

2008 (20)

Retrospective

cohort

Brazil Median,

25.5 mo

(trans-

mitters) vs.

22.3 mo

(nontransmitters)

Transmitters vs.

nontransmitters

Women, 72% (index

cases); IDUs, 57.7%;

unprotected sex,

91%; STD diagnosis,

23.6%

4500 screened

retrospectively, 93

enrolled (56 enrolled

retrospectively plus

37 enrolled

prospectively)

Not reported Not reported Transmissions, ART vs. no ART:

0/41 vs. 6/52

Median viral load, transmitters vs.

nontransmitters: 24 082

(range, 1479 to 100 539) vs.

4583 (range, 78 to 47 974);

P⫽0.042

Fair

Musicco

et al,

1994 (21)

Prospective

cohort

Italy Mean, 2 y

(740 PYs)

Zidovudine vs. no

zidovudine

Mean age, 26 y;

women, 100%;

median duration of

relationship with

HIV-positive partner,

3 y; consistent

condom use, 56%;

regular sexual

intercourse, 53%; anal

sex, 15%; oral sex,

48%

Number screened not

reported, 525

eligible, 436

enrolled, number

withdrew and

percentage analyzed

unclear; data from

103 PYs excluded

Not reported Not reported Seroconversions, zidovudine vs.

no zidovudine: 3.8/100 PYs

vs. 4.4/100 PYs; adjusted RR,

0.5 (95% CI, 0.1 to 0.9)

Fair

Continued on following page

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Appendix Table 2—Continued

Study, Year

(Reference)

Study Design

Details

Location Duration of

Follow-up

Treatment and

Comparison Groups

Demographic

Characteristics/Baseline

Disease

Participants Virologic Response CD4 Cell Count

Response

Outcomes Quality

Rating

Reynolds

et al,

2011 (22)

Retrospective

cohort

Uganda Median, 1.57 y

before ART

initiation and

1.54 y after

ART

initiation

Pre-ART vs. post-ART

transmission

Male index partner, 58%

(142/250); consistent

condom use, 4%;

polygamous husbands,

20%

15 000 screened, 250

eligible, 250 enrolled

6 months: 71.4%

(20/28) below

detectable limit and

remaining 28.6%

(8/28) below 2000

copies/mL

12 months: 85.2%

(23/27) below 400

copies/mL, 14.8%

(4/27) ranging from

2293 to 672 513

copies/mL

24 months: 100%

(28/28) below 400

copies/mL

Not reported Transmission:

Pre-ART: 9.2/100 PYs (95%

CI, 6.59 to 12.36/100 PYs)

Post-ART: 0/53.6 PYs (95% CI

⫺11.91 to 16.38/53.6 PYs);

P⫽0.010

Fair

Sullivan

et al,

2009 (23)

Retrospective

cohort

(abstract

only)

Rwanda and

Zambia

Median, 512 d

(1.4 y)

ART vs. no ART Not reported 2993 enrolled Not reported Not reported Transmission, ART vs. no ART:

4/175 (0.7/100 PYs) vs.

171/175 (3.4/100 PYs); RR,

0.21 (95% CI, 0.08 to 0.59);

HR, 0.21 (95% CI, 0.09 to

0.52)

Could not

assess

for

quality

Lu et al,

2010 (24)

Retrospective

cohort

China Median, 2.8 y ART vs. no ART Mean age, 44 y;

women, 43%; regular

sexual intercourse,

84%; condom use,

78%; monogamous,

99%

4348 screened,

4301 eligible,

1927 enrolled,

no withdrawals,

100% analyzed

Not reported Not reported Seroconversions, ART vs. no ART:

66/1369 (4.8%) vs. 18/558

(3.2%); univariate RR, 0.76

(95% CI, 0.45 to 1.28)

Fair

ART ⫽antiretroviral therapy; HR ⫽hazard rate; HSV ⫽herpes simplex virus; IDU ⫽injection drug user; IQR ⫽interquartile range; IR ⫽incidence rate; ND ⫽not detectable; PY ⫽person-year; RCT ⫽randomized,

controlled trial; RR ⫽relative risk; STD ⫽sexually transmitted disease.

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Appendix Table 3. Cardiovascular Events and ART Use

Study, Year

(Reference)

Study

Name

Duration

Follow-up

Population Characteristics Interventions Adjusted Variables

for Statistical

Analysis

MI Other Cardiovascular

Events/Composite Outcomes

Bedimo et al,

2011 (54)

NA Median, 4 y Participants: 19 424

Median age: 46 y

Men: 98%

Smokers: 29%

Diabetes: 13%

Hypertension: 38%

Hypercholesterolemia: 26%

Chronic kidney disease: 8%

HCV infection: 32%

Any ART (n⫽14 063) Age, diabetes,

hypertension,

hypercholesterolemia,

and smoking

Adjusted HR for cumulative MI exposure (95% CI):

Abacavir: 1.18 (0.92 to 1.5)

Other NRTIs: 0.99 (0.87 to 1.11)

Mono- or dual-ART: 1.29 (1.10 to 1.52)

Not reported

Worm et al,

2010 (53)

DAD Study Median, 6 y Participants: 33 308

Median age: 44 y

Women: 26%

Race: not reported

Framingham risk, total

population:

Low: 53%

Moderate: 15%

High: 4%

Framingham risk, patients with

MI:

Low: 26%

Moderate: 30%

High: 18%

Framingham risk, patients

without MI:

Low: 54%

Moderate: 15%

High: 4%

PIs: nelfinavir (n⫽10 370),

indinavir (n⫽11 985),

lopinavir–ritonavir

(n⫽9995), and saquinavir

(n⫽8070)

NRTIs: zidovudine

(n⫽25 754), didanosine

(n⫽13 851), zalcitabine

(n⫽4951), stavudine

(n⫽16 840), lamivudine

(n⫽28 835), abacavir

(n⫽12 511), and tenofovir

(n⫽13 100)

NNRTIs: nevirapine

(n⫽12 194) and efavirenz

(n⫽13 522)

Age, sex, HIV

transmission

group, race,

calendar year,

cohort, smoking,

family history of

CVD, previous CV

event, BMI, and

exposure to other

ART

Adjusted relative rate (95% CI):

Cumulative PI use:

Nelfinavir: 1.04 (0.98 to 1.11)

Indinavir: 1.12 (1.07 to 1.18)

Lopinavir–ritonavir: 1.13 (1.05 to 1.21)

Saquinavir: 1.04 (0.98 to 1.11)

Per year of PI exposure:

Indinavir: 1.11 (1.05 to 1.18)

Indinavir plus ritonavir: 1.18 (1.07 to 1.30)

Saquinavir: 1.07 (0.97 to 1.20)

Saquinavir plus ritonavir: 1.06 (0.97 to 1.14)

Adjusted relative rate for cumulative NRTI use (95% CI):

Zidovudine: not significant (data not reported)

Didanosine: 1.41 (1.09 to 1.82)

Zalcitabine: not significant (data not reported)

Stavudine: not significant (data not reported)

Lamivudine: not significant (data not reported)

Abacavir: 1.07 (1.00 to 1.14)

Tenofovir: 1.04 (0.91 to 1.18)

Recent NRTI use:

Abacavir: 1.7 (1.17 to 2.47)

Tenofovir: 1.14 (0.85 to 1.53)

Cumulative NNRTI use:

Nevirapine: 0.97 (0.92 to 1.03)

Efavirenz: 1.02 (0.96 to 1.08)

Not reported

Sabin et al,

2008 (52)

DAD Study Median, 5 y Participants: 33 347

Mean age: 43 y

Women: 26%

Framingham risk, patients with

MI:

Low: 22% (113/517)

Moderate: 26% (134/517)

High: 23% (120/517)

Unknown: 29% (150/517)

NRTIs (numbers not reported):

zidovudine, didanosine,

stavudine, lamivudine,

abacavir

Age, sex, risk group,

race, cohort, BMI,

family history of

CVD, smoking,

previous CV

event, year, and

cumulative

exposure to other

ART

Adjusted relative rate (95% CI):

Cumulative exposure:

Zidovudine: 1.04 (0.99 to 1.09)

Didanosine: 1.00 (0.93 to 1.07)

Stavudine: 1.02 (0.95 to 1.09)

Lamivudine: 0.99 (0.93 to 1.06)

Abacavir: 1.00 (0.92 to 1.08)

Recent exposure:

Zidovudine: 1.22 (0.82 to 1.81)

Didanosine: 1.53 (1.10 to 2.13)

Stavudine: 1.22 (0.84 to 1.77)

Lamivudine: 1.69 (1.02 to 2.8)

Abacavir: 1.94 (1.48 to 2.55)

Past exposure:

Zidovudine: 1.29 (0.89 to 1.85)

Didanosine: 1.08 (0.84 to 1.39)

Stavudine: 1.24 (0.93 to 1.66)

Lamivudine: 1.45 (0.88 to 2.4)

Abacavir: 1.29 (0.94 to 1.77)

Adjusted relative rates for MI, CV

death, or invasive CV

procedure (95% CI):

Cumulative exposure:

Zidovudine: 1.04 (1.00 to 1.08)

Didanosine: 0.99 (0.94 to 1.05)

Stavudine: 1.04 (0.99 to 1.10)

Lamivudine: 1.01 (0.96 to 1.06)

Abacavir: 1.03 (0.96 to 1.10)

Any recent exposure:

Zidovudine: 0.98 (0.79 to 1.21)

Didanosine: 1.40 (1.11 to 1.77)

Stavudine: 0.99 (0.78 to 1.25)

Lamivudine: 1.15 (0.91 to 1.44)

Abacavir: 1.63 (1.3 to 2.04)

Continued on following page

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Appendix Table 3—Continued

Study, Year

(Reference)

Study

Name

Duration of

Follow-up

Population Characteristics Interventions Adjusted Variables

for Statistical

Analysis

MI Other Cardiovascular

Events/Composite Outcomes

Friis-Møller et al,

2007 (51) and

2003 (50)

DAD Study Median, 5 y Participants: 23 437

Median age: 39 y

Women: 24%

Current/former smokers: 61%

Hypertension: 14%

Dyslipidemia: 42%

Any ART (n⫽21 921),

PIs (n⫽18 919), and

NNRTIs (n⫽15 142)

Model 1: Age, sex,

cohort, HIV

transmission

group, race, age,

BMI, family

history of CVD,

smoking, previous

CV event, and

calendar year

Model 2: All from

model 1 plus total

cholesterol level,

HDL cholesterol

level, hypertension,

and diabetes

ART use:

Incidence: 97 events/16 805 PYs (5.77/1000 PYs)

Adjusted relative rate, model 1 (95% CI): 1.16 (1.09 to

1.23)

Adjusted relative rate for PI use (95% CI):

Model 1: 1.16 (1.10 to 1.23)

Model 2: 1.10 (1.04 to 1.18)

Excluding patients exposed to NRTIs: 1.15 (1.06 to

1.25)

Adjusted relative rate for NRTI use (95% CI):

Model 1: 1.05 (0.98 to 1.13)

Model 2: 1.00 (0.93 to 1.09)

Excluding patients exposed to PIs: 0.94 (0.74 to 1.19)

Not reported

Obel et al,

2010 (55)

Danish HIV

cohort

study

Mean, 6 y Participants: 2952

Median age: 39 y

Men: 76%

CV risk factors: not reported

Triple NRTI regimen, including

abacavir, and NNRTI or PI

regimen, including abacavir

Specific drugs: abacavir

(n⫽1761), zidovudine

(n⫽2711), lamivudine

(n⫽2867), stavudine

(n⫽1031), didanosine

(n⫽813)

Age, sex, year of

diagnosis, year of

ART initiation,

CD4 cell count,

viral load, race,

injection drug use,

use of other

antiretrovirals,

and comorbid

conditions

Abacavir use vs. nonuse:

Any abacavir exposure: Incidence, 2.4/1000 PYs (95%

CI, 1.7 to 3.4/1000 PYs) vs. 5.7/1000 PYs (95% CI,

4.1 to 7.9/1000 PYs); adjusted RR, 2.0 (95% CI, 1.1

to 3.6)

RR (95% CI):

Actual abacavir use: 1.95 (1.05 to 3.6)

Early abacavir use: 2.37 (0.88 to 6.36)

Abacavir as part of triple NRTI: 1.91 (0.88 to 4.17)

Abacavir with NNRTI or PI: 2.06 (1.06 to 4.01)

Abacavir initiated ⱕ2 y of ART: 1.77 (0.82 to 3.82)

Abacavir initiated ⬎2 y of ART: 2.66 (1.31 to 5.39)

Not reported

Ribaudo et al,

2011 (56)

NA Median, 3 y Participants: 5056 (1122 with

6-y data)

Median age: 37 y

Female: 18%

White: 40%

Black: 36%

Hispanic: 21%

Previous injection drug use:

10%

ⱖ2 CVD risk factors: 15%

CVD 10-y risk score ⱕ10: 5%

Abacavir (n⫽1704) and no

abacavir (n⫽3352)

Age, sex, race, CVD

risk factors,

smoking, and

family history

of CVD

Adjusted HR, abacavir use vs. nonuse (95% CI):

1 y: 0.7 (0.2 to 2.6)

6 y: 0.6 (0.3 to 1.4)

Adjusted HR for serious CVD

events, abacavir use vs.

nonuse (95% CI):

1 y: 1.1 (0.5 to 2.1)

6 y: 0.9 (0.5 to 1.3)

ART ⫽antiretroviral therapy; BMI ⫽body mass index; CV ⫽cardiovascular; CVD ⫽cardiovascular disease; DAD ⫽Data Collection on Adverse Events of Anti-HIV Drugs; HCV⫽hepatitis C virus; HDL ⫽high-density

lipoprotein; HR ⫽hazard ratio; MI ⫽myocardial infarction; NA ⫽not applicable; NNRTI ⫽nonnucleoside reverse transcriptase inhibitor; NRTI ⫽nucleoside reverse transcriptase inhibitor; PI ⫽protease inhibitor, PY ⫽

person-year; RR ⫽relative risk.

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Evidence-based recommendations for the diagnosis, treatment, functional rehabilitation, and follow-up of people over 7 years of age with low vision

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Feb 2025
J ALZHEIMERS DIS

Background Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies. Objective To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes. Methods We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies. Results Thirty studies met our eligibility criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR] = 1.38, 95% confidence interval [CI]: 1.19–1.59, I² = 28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio [HR] = 1.17, 95% CI: 1.00–1.38, I² = 0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR = 1.34, 95% CI: 1.11–1.61, I² = 63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR = 0.97, 95% CI: 0.90–1.04, I² = 51.5%) or age-related macular degeneration (7,800,692 participants, > 2,559 cases, HR = 1.15, 95% CI: 0.88–1.50, I² = 91.0%) and risk of dementia, respectively. Conclusion As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation.

Neurofibromatosis Type 1 (NF1)–Related Ocular Signs: New Insights on Their Prevalence, Incidence, and Genotype-Phenotype Correlation in NF1 Children

Article

Mar 2025
AM J OPHTHALMOL

Chapter 22. Neurocognitive Disorders

Chapter

Dec 2024

Principles of Screening for Disease and Health Risk Factors in the Emergency Department

Article

Aug 2022
ANN EMERG MED

The emergency department serves as a critical access point to the health system for many patients, especially those with limited resources. Screening for disease or risk factors for poor health outcomes can potentially improve both individual and population health. Screening initiatives should focus on evidence-based strategies and take local epidemiology and ED capacity into consideration. Initiatives should strive for community support and transparency with patients. They should also be financially sustainable for those involved. Screening can identify patients who can then be counseled, provided with prophylaxis or treatment, or referred to external resources. Through screening and intervention, the ED can serve as a vital contributor to individual and population health.

The DAD Study Group. Combination antiretroviral therapy and the risk of myocardial infarction

Article

Full-text available

Nov 2003

Background: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction. Methods: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Results: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P<0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction. Conclusions: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use. However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits from antiretroviral treatment.

Class of antiretroviral drugs and the risk of myocardial infarction

Article

Apr 2007

BACKGROUND:We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association of cumulative exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors with the risk of myocardial infarction.METHODS:We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus. The incidence rates of myocardial infarction during the follow-up period were calculated, and the associations between myocardial infarction and exposure to protease inhibitors or nonnucleoside reverse-transcriptase inhibitors were determined.RESULTS:Three hundred forty-five patients had a myocardial infarction during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively.CONCLUSIONS:Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.

The HIV Incidence Surveillance Group. Estimated HIV incidence in the United States 2006-2009

Article

Jan 2011
PLOS ONE

HIV surveillance--United States, 1981-2008.

Article

Jun 2011

Centers for Disease Control and Prevention (CDC

Within 1 year of the initial report in 1981 of a deadly new disease that occurred predominantly in previously healthy persons and was manifested by Pneumocystis carinii pneumonia and Kaposi's sarcoma, the disease had a name: acquired immune deficiency syndrome (AIDS). Within 2 years, the causative agent had been identified: human immunodeficiency virus (HIV). On the 30th anniversary of the epidemic, to characterize trends in HIV infection and AIDS in the United States during 1981-2008, CDC analyzed data from the National HIV Surveillance System. This report summarizes the results of that analysis, which indicated that, in the first 14 years, sharp increases were reported in the number of new AIDS diagnoses and deaths among persons aged≥13 years, reaching highs of 75,457 in 1992 and 50,628 in 1995, respectively. With introduction of highly active antiretroviral therapy, AIDS diagnoses and deaths declined substantially from 1995 to 1998 and remained stable from 1999 to 2008 at an average of 38,279 AIDS diagnoses and 17,489 deaths per year, respectively. Despite the decline in AIDS cases and deaths, at the end of 2008 an estimated 1,178,350 persons were living with HIV, including 236,400 (20.1%) whose infection was undiagnosed. These findings underscore the importance of the National HIV/AIDS Strategy focus on reducing HIV risk behaviors, increasing opportunities for routine testing, and enhancing use of care (1).

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team.

Article

Jan 1997
NEW ENGL J MED

The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. METHODS: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine (or stavudine) and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. RESULTS: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine, and lamivudine (6 percent) than with zidovudine and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P=0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. CONCLUSIONS: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine.

Expanded HIV Screening in the United States: Effect on Clinical Outcomes, HIV Transmission, and Costs

Article

Dec 2006

A David Paltiel

Design: Cost-effectiveness analysis linking simulation models of HIV screening to published reports of HIV transmission risk, with and without antiretroviral therapy. Data Sources: Published randomized trials, observational cohorts, national cost and service utilization surveys, the Red Book, and previous modeling results. Target Population: U.S. communities with low to moderate HIV prevalence (0.05% to 1.0%) and annual incidence (0.0084% to 0.12%).

Timing of HAART Initiation and Clinical Outcomes in Human Immunodeficiency Virus Type 1 Seroconverters

Article

Sep 2011
ARCH INTERN MED

Writing Committee for the CASCADE Collaboration

Background: To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL. Methods: In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs). Results: Of 9455 patients with 52,268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively. Conclusion: Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.

Antiretroviral Treatment of Men Infected with Human Immunodeficiency Virus Type 1 Reduces the Incidence of Heterosexual Transmission. Italian Study Group on HIV Heterosexual Transmission

Article

Sep 1994
ARCH INTERN MED

Objective: To determine the incidence of heterosexual human immunodeficiency virus type 1 disease transmission and the effect of zidovudine therapy on this risk of transmission. Design: A cohort of 436 monogamous seronegative female sexual partners of human immunodeficiency virus type 1-infected males was followed up for 740 person-years with regular structured interviews and laboratory tests. Patients: At enrollment of the women, 50% of their infected partners had one or more signs of disease progression (symptoms of acquired immunodeficiency syndrome, p24 antigen positivity, or CD4+ cell counts lower than 0.4 x 10(9)/L) and 15% were treated with zidovudine. Main outcome measure: Incidence rates of seroconversion were calculated and relative risks were estimated as incidence rate ratios. Results: Twenty-seven women seroconverted during follow-up, and the incidence of seroconversion was 3.7 per 100 person-years. Seroconversion was about six times more frequent (relative risk, 5.8; 95% confidence interval, 2.2 to 15.3) in couples not using condoms. Men with signs of disease progression transmitted infection to their partners more frequently and were more frequently treated with zidovudine. When the risk of transmission was estimated accounting for disease progression, the rate of transmission in zidovudine-treated men was lower than in untreated men (relative risk, 0.5; 95% confidence interval, 0.1 to 0.9). Conclusion: Treatment of human immunodeficiency virus type-1 infected men with zidovudine reduces, but does not eliminate, heterosexual transmission of infection. Behavioral counseling that encourages sexual practices with a lower risk of transmission remains the most important method of prevention.

When to Initiate Highly Active Antiretroviral Therapy: A Cohort Approach

Article

Apr 2003
AM J EPIDEMIOL

Linda Ahdieh-Grant

The appropriate immunologic stage of human immunodeficiency virus infection at which to initiate highly active antiretroviral therapy (HAART) among asymptomatic persons is a core question. A cohort approach using longitudinal data from the US Multicenter AIDS Cohort Study was used to mimic a clinical trial to assess the risk of acquired immunodeficiency syndrome (AIDS) by timing of therapy. Three treatment groups were defined according to CD4⁺ count (cells/µl) at HAART initiation between July 1995 and January 2000: <200 (deferral to <200, n = 127), 200–349 (deferral to 200–349, n = 130), and 350–499 (immediate treatment, n = 92). Survival analysis was used to compare time to AIDS between groups from the index visit until July 2000. The index visit for the immediate group was the one prior to HAART initiation. For the deferral groups, the index visit was a randomly selected, pre-HAART, AIDS-free visit after July 1990 at which CD4⁺ counts were 350–499 cells/µl. This strategy accounted for lead time bias. Compared with immediate treatment, the relative hazards of AIDS were 2.68 (p = 0.003) and 1.05 (p = 0.897) for deferral to <200 cells/µl and 200–349 cells/µl, respectively. These results support recent US public health guidelines for deferring HAART initiation until a count of <350 cells/µl. Furthermore, results suggest a potential threshold for HAART initiation in the neighborhood of 275 cells/µl.

Rates of Disease Progression by Baseline CD4 Cell Count and Viral Load After Initiating Triple-Drug Therapy

Article

Nov 2001

Robert S. Hogg

Context Current recommendations for initiation of antiretroviral therapy in patients infected with human immunodeficiency virus type 1 (HIV) are based on CD4 T-lymphocyte cell counts and plasma HIV RNA levels. The relative prognostic value of each marker following initiation of therapy has not been fully characterized.Objective To describe rates of disease progression to death and AIDS or death among patients starting triple-drug antiretroviral therapy, stratified by baseline CD4 cell count and HIV RNA levels.Design, Setting, and Participants Population-based analysis of 1219 antiretroviral therapy–naive HIV-positive men and women aged 18 years or older in British Columbia who initiated triple-drug therapy between August 1, 1996, and September 30, 1999.Main Outcome Measure Cumulative mortality rates from the initiation of triple-drug antiretroviral therapy to September 30, 2000, determined using various CD4 cell and plasma HIV RNA thresholds.Results As of September 30, 2000, 82 patients had died of AIDS-related causes, for a crude AIDS-related mortality rate of 6.7%. The product limit estimate (SE) of the cumulative mortality rate at 12 months was 2.9% (0.5%). In univariate analyses, a prior diagnosis of acquired immunodeficiency syndrome (AIDS), CD4 cell count, use of protease inhibitors, and HIV RNA level were associated with mortality. There was no difference in mortality by age or sex. Only CD4 cell count remained statistically significant in the multivariate analysis. After controlling for AIDS, protease inhibitor use, and plasma HIV RNA level at baseline, patients with CD4 cell counts of less than 50/µL were 6.67 (95% confidence interval [CI], 3.61-12.34) times and those with counts of 50/µL to 199/µL were 3.41 (95% CI, 1.93-6.03) times more likely to die than those with counts of at least 200/µL.Conclusion Our data demonstrate uniformly low rates of disease progression to death and AIDS or death among patients starting antiretroviral therapy with CD4 cell counts of at least 200/µL. In our study, disease progression to death and AIDS or death was clustered among patients starting therapy with CD4 cell counts less than 200/µL.

Screening for HIV: Systematic Review to Update the 2005 U.S. Preventive Services Task Force Recommendation

Abstract and Figures

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