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Antiretroviral Therapy for the Prevention of HIV Transmission: What Will It Take?

Author(s): Margaret L. McNairy and Wafaa M. El-Sadr

Source: Clinical Infectious Diseases , 1 April 2014, Vol. 58, No. 7 (1 April 2014), pp. 1003- 1011

Published by: Oxford University Press

Stable URL: http://www.jstor.com/stable/24031689

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INVITED ARTICLE HIV/AIDS HIV/AIDS

Kenneth H. Mayer, Section Editor

Antiretroviral Therapy for the Prevention of HIV Transmission: What Will It Take?

Margaret L. McNairy12 and Wafaa M. El-Sadr13

'Mailman School of Public Health, ICAP at Columbia University, Weill-Cornell Medical College and Department of Epidemiology, Mailman School

of Public Health, Columbia University, New York, New York

(See the Editorial Commentary by De Cock on pages 1012-14.)

The evidence in support of use of antiretroviral therapy (ART) for prevention of human immunodeficiency virus (HIV) transmission is encouraging and has stimulated optimism for achieving a dramatic change in the trajectory of the HIV epidemic. Yet, there are substantial challenges that, if not addressed, could be the Achilles' heel for this concept. These challenges require strengthening every step of the HIV care continuum, including expansion of HIV testing to reach all those with HIV infection, effective linkage to and retention in care, timely initiation of ART, and high levels of treatment adherence with viral load suppression. Also impor tant is the identification of individuals with acute HIV infection whose contribution to HIV transmission may be substantial. Implementation research is needed to identify strategies that address these challenges and to de termine the efficacy of ART for prevention in key populations as well as to evaluate the effectiveness of combi nation strategies for HIV prevention at the population level.

Keywords. HIV; prevention; antiretroviral therapy.

Over the past 2 decades, there have been significant infections in children [2], The evidence for efficacy of achievements in the response to the global human im- ART for prevention of HIV transmission has generated

munodeficiency virus (HIV) epidemic, particularly in tremendous optimism and has been hailed as a turning sub-Saharan Africa (SSA), the epicenter of the epidemic. point in the epidemic. From 2002 to the end of 2010, the number of individuals

with access to combination antiretroviral therapy (ART)

has increased from approximately 200 000 to >8 million EVIDENCE IN SUPPORT OF USE OF persons in low- and middle-income countries [1, 2], ANTIRETROVIRAL DRUGS FOR HIV Scale-up of ART has been associated with a decrease in PREVENTION mortality as well as increased worker productivity, in creased school attendance, socioeconomic status, and The HPTN 052 study reported a 96% decrease in linked

improved family income status [2-5], HIV transmission among stable serodiscordant hetero Despite these achievements, the HIV epidemic re- sexual couples in whom the HIV-positive partner was

mains substantial with an estimated 2.5 million new in- initiated on ART at CD4+ counts between 350 and

fections occurring per year including 330 000 new 550 cells/pL as compared to those who initiated ART at CD4+ counts between 200 and 250 cells/pL [6]. Ob servational studies have also supported the role of ART

for prevention of HIV transmission among serodis Received 2 May 2013; accepted 18 October 2013; electronically published 14

January 2014.

Correspondence: Margaret McNairy, MD, MSc, ICAP at Columbia University, cordant couples in Taiwan, Spain, Brazil, China, and

SSA [7-13]. Ecological studies also have provided sup Mailman School of Public Health, 722 W 168th St, 7th Floor, New York, NY

10032 ([email protected]).

Clinical Infectious Diseases 2014;58<7):1003-11 Port for the role of ART for Prevention. Studies from ©The Author 2014. Published by Oxford University Press on behalf of the Infectious San Francisco and British Columbia reported a decrease

Diseases Society of America. All rights reserved. For Permissions, please e-mail: & number of ngw fflv infecüons associated with [email protected].

D01:10.1093/cid/ciu0i8 expanded ART use by HIV-infected individuals in

HIV/AIDS • CID 2014:58 (1 April) • 1003

©The Author2014. Pi

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© Unaware of HIV Status

© © © Inability to Achieve and Maintain Viral Suppression

those communities [14, 15]. A more recent study from South Challenges for ART for Prevention Africa demonstrated that increased ART coverage for those el

igible based on national guidelines was associated with a de crease in HIV incidence [16].

Modeling studies have provided support for the premise that

expanded use of ART for prevention could substantially change Diagnosis of HIV Infection the trajectory of the HIV epidemic [17]. However, concerns

have been raised regarding the optimistic assumptions used in

some models and that, in general, these models did not ade- £ Failure of HIV-Positive Patients to Link to Care quately account for risk of development or drug-resistant virus [17-19], In response, the HIV Modeling Consortium sug

gested that future models focus on the effects of ART for pre- Late Initiation of ART vention in the short term, which may provide useful information in financial and policy planning, and incorporate

real-life HIV program performance [19].

Use of antiretroviral drugs by HIV-negative individuals, although not the focus of this overview, has also been shown

to have promising results for prevention of HIV acquisition. Figure 1. Challenges for antiretroviral therapy (ART) for prevention of „ il- i . i_ cr „Tir human immunodeficiency virus (HIV) transmission. Preexposure prophylaxis was shown to be efficacious in HIV

negative men who have sex with men (MSM) [20], HIV-negative

partners in discordant couples [21], women in Botswana [22],

and intravenous drug users in Thailand [23]. However, other HIV Testing

studies have not confirmed this finding, largely thought to be HIV testing is the first and critical step for HIV prevention and

due to limited adherence (ie, FemPreP, VOICE studies) [24,25], treatment efforts. In countries with high HIV prevalence, uni

versal access to HIV testing is recommended [30], yet <40% of

THE CALL TO IMPLEMENT ART FOR HIV PLWH in SSA know their status, with proportionally fewer men PREVENTION than women [31]. In the United States, HIV testing is recom

mended as an opt-out test, and high-risk groups are encouraged

In June 2011, in view of the promise of ART for prevention, the for repeat testing at least annually [32]. In 2008, as reported by

global community embraced an ambitious target of achieving the National HIV Surveillance System, 80% of the estimated 1.2

15 million persons living with HIV (PLWH) on treatment by million PLWH in the United States had been diagnosed [33],

2015 along the path to what has been referred to as reaching Yet, within specific groups at substantial risk such as MSM, an "AIDS-free generation" [26], Although the approach to be there is a lag in repeat testing to promptly identify newly infect -

used for expansion of ART use for prevention may differ in a ed individuals [34].

generalized epidemic such as in southern Africa from that Expanded testing may be achieved through increased access used in a concentrated epidemic within key populations such to testing through community, home, provider-initiated, and

as the United States, the need for attention to various steps in self-testing and through increased demand for tests via ampli

the HIV care continuum is equally important [27], Intervention fied HIV awareness and dissemination of information regard

ât each of these steps form the combination strategy that is part ing the benefits of knowing one's HIV status. The Project

and parcel of "treatment as prevention" [28], and each step must Accept (HPTN 043) study demonstrated a 9-fold higher vol

be implemented with high coverage and quality to achieve the ume of HIV testing through use of enhanced community promise of the overall strategy (Figure 1) [29]. based testing in 48 communities in South Africa, Tanzania,

Zimbabwe, and Thailand compared with clinic-based stan THE ACHILLES' HEEL OF ART FOR PREVENTION dard counseling and testing, with an increase of testing by

men by 45% [35]. Home testing has also been successfully im

To advance the strategy of ART for prevention, there is the need plemented in several countries and offers the opportunity for

to be cognizant of the vulnerabilities in this strategy—what we reaching entire families and households [36, 37]. HIV self call the "Achilles' heel." In this context, the expression refers to testing may also be a novel way to expand testing. A systematic

a critical weakness that can threaten the overall potential of ART review of 21 studies on self-testing for HIV in high- and low

for prevention (Table 1). This article presents an overview of risk groups reported that both supervised and unsupervised these vulnerabilities. self-testing strategies were highly acceptable, preferred to

1004 • CID 2014:58 (1 April) • HIV/AIDS

Challenges for ART for Prevention

e © o o ©

Unaware of HIV Status

Late Diagnosis of HIV Infection

Failure of HIV-Positive Patients to Link to Care

Late Initiation of ART

Inability to Achieve and Maintain Viral Suppression

Figure 1. Challenges for antiretroviral therapy (ART) for prevention of

human immunodeficiency virus (HIV) transmission.

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Table 1. Antiretroviral Therapy for Treatment and Prevention: Potential Solutions for Every Achilles' Heel

Achilles' Heel Challenges Potential Solutions

HIV testing • Suboptimal testing coverage for high prevalence settings and for key populations

• Infrequent retesting for at-risk populations • Stigma and discrimination • Fear of knowing status and/or denial • Unaware of importance of knowing status

Linkage to care • Separate facilities and staff provide testing vs care and treatment services

• Structural barriers: distance, transport costs, clinic wait times

• Behavioral barriers • Biomedical barriers

• Lack of required indicator reporting

Enrollment in care • Late HIV diagnosis at advanced • Timely HIV diagnosis but late linkage to HIV stages of HIV care due to stigma, fear, lack of knowledge, disease distance from clinic, unwelcoming

environment in clinics and attitudes by providers

ART initiation • Obstacles to determining eligibility through CD4+ count assays and/or knowledge of WHO staging system

• Delay in initiation of eligible patients on ART • Patient refusal to initiate ART

• Stock-out of antiretroviral drugs • Paucity of trained, skilled healthcare workers

Retention in care • Suboptimal retention in PLWH who have not started ART as well as those on ART

• Lower retention rates in PLWH who are

asymptomatic with higher CD4+ count • Structural barriers of time to clinic, transport

costs, lost wages, child care responsibilities • Limited of real-time systems to track patients

who miss appointments

Viral load • Suboptimal medication adherence suppression • Limited availability of viral load testing

• Discordancy between undetectable viral load in plasma and genital track/semen

• Limited availability of resistance testing • Limited availability of second and third-line

ART regimens

Expanded community-based or home-based testing Expanded provider-initiated testing at health facilities Increase in uptake of self-tests in at-risk groups, among couples and others

Community engagement to destigmatize HIV, promote HIV testing, and provide information on availability of HIV care and prevention programs

Integration of testing and treatment clinics/programs Same-day clinic appointments for those found to be HIV infected Point of care CD4+ count testing at time of HIV testing Case managers/peer educators to navigate PLWH to first HIV clinic appointments Motivational counseling Increased patient awareness of importance of linkage to care for health benefits

Requiring testing sites to report on linkage outcomes Implementation research to evaluate structural, behavioral, and biomedical interventions

Earlier diagnosis of HIV through expanded HIV testing efforts including community- and home-based testing efforts Linkage interventions as above Community engagement to disseminate information regarding importance of HIV care for PLWH and motivate such individuals to enroll in care

Structural interventions to enhance attitudes among healthcare workers and modify clinic procedures to become more convenient and welcoming Decentralization of services in order to bring clinical services closer to where PLWH are situated

Attention to the needs of key populations through establishment of special programs that meet these unique needs

Routine monitoring and identification of ART-eligible patients who are in care and need ART initiation

Laboratory specimen and result transport and transmission systems Use of point-of-care CD4+ cell count machines Personalized counseling sessions for patients who refuse ART Strengthened supply chain management and forecasting of ART needs

Training and mentorship of providers on WHO staging criteria to determine ART eligibility in the absence of CD4+ testing Expanded healthcare workforce including nurse initiation of ART Research to determine motivators and impediments for initiation of ART in PLWH with early HIV disease

Implementation research on HIV program modifications to strengthen retention among PLWH who have not yet initiated ART and those on ART

Implementation research on structural interventions to promote retention, particularly among PLWH with early HIV disease Utilization of mobile technology, peer educators, and/or community strategies to track PLWH who miss appointments within several days of appointment date Engagement of community resources to facilitate retention of PLWH

Interventions to promote medication adherence for PLWH on ART, particularly those who initiate ART at earlier stages of disease

Choice of regimens that are well tolerated and convenient Increased availability of viral load monitoring and resistance testing Use of viral load monitoring and viral resistance assays, if available

Implementation research on interventions to support adherence and on optimal options for monitoring of PLWH on ART Research on transmission risk in patients with undetectable plasma viral load

HIV/AIDS • CID 2014:58 (1 April) • 1005

Achilles' Heel Challenges Potential Solutions

HIV testing • Suboptimal testing coverage for high prevalence settings and for key populations

• Infrequent retesting for at-risk populations • Stigma and discrimination • Fear of knowing status and/or denial • Unaware of importance of knowing status

Linkage to care • Separate facilities and staff provide testing vs care and treatment services

• Structural barriers: distance, transport costs, clinic wait times

• Behavioral barriers • Biomedical barriers

• Lack of required indicator reporting

Enrollment in care • Late HIV diagnosis at advanced • Timely HIV diagnosis but late linkage to HIV stages of HIV care due to stigma, fear, lack of knowledge, disease distance from clinic, unwelcoming

environment in clinics and attitudes by providers

ART initiation • Obstacles to determining eligibility through CD4+ count assays and/or knowledge of WHO staging system

• Delay in initiation of eligible patients on ART • Patient refusal to initiate ART

• Stock-out of antiretroviral drugs • Paucity of trained, skilled healthcare workers

Retention in care • Suboptimal retention in PLWH who have not started ART as well as those on ART

• Lower retention rates in PLWH who are

asymptomatic with higher CD4+ count • Structural barriers of time to clinic, transport

costs, lost wages, child care responsibilities • Limited of real-time systems to track patients

who miss appointments

Viral load • Suboptimal medication adherence suppression • Limited availability of viral load testing

• Discordancy between undetectable viral load in plasma and genital track/semen

• Limited availability of resistance testing • Limited availability of second and third-line

ART regimens

Expanded community-based or home-based testing Expanded provider-initiated testing at health facilities Increase in uptake of self-tests in at-risk groups, among couples and others

Community engagement to destigmatize HIV, promote HIV testing, and provide information on availability of HIV care and prevention programs

Integration of testing and treatment clinics/programs Same-day clinic appointments for those found to be HIV infected Point of care CD4+ count testing at time of HIV testing Case managers/peer educators to navigate PLWH to first HIV clinic appointments Motivational counseling Increased patient awareness of importance of linkage to care for health benefits

Requiring testing sites to report on linkage outcomes Implementation research to evaluate structural, behavioral, and biomedical interventions

Earlier diagnosis of HIV through expanded HIV testing efforts including community- and home-based testing efforts Linkage interventions as above Community engagement to disseminate information regarding importance of HIV care for PLWH and motivate such individuals to enroll in care

Structural interventions to enhance attitudes among healthcare workers and modify clinic procedures to become more convenient and welcoming Decentralization of services in order to bring clinical services closer to where PLWH are situated

Attention to the needs of key populations through establishment of special programs that meet these unique needs

Routine monitoring and identification of ART-eligible patients who are in care and need ART initiation

Laboratory specimen and result transport and transmission systems Use of point-of-care CD4+ cell count machines Personalized counseling sessions for patients who refuse ART Strengthened supply chain management and forecasting of ART needs

Training and mentorship of providers on WHO staging criteria to determine ART eligibility in the absence of CD4+ testing Expanded healthcare workforce including nurse initiation of ART Research to determine motivators and impediments for initiation of ART in PLWH with early HIV disease

Implementation research on HIV program modifications to strengthen retention among PLWH who have not yet initiated ART and those on ART

Implementation research on structural interventions to promote retention, particularly among PLWH with early HIV disease Utilization of mobile technology, peer educators, and/or community strategies to track PLWH who miss appointments within several days of appointment date Engagement of community resources to facilitate retention of PLWH

Interventions to promote medication adherence for PLWH on ART, particularly those who initiate ART at earlier stages of disease

Choice of regimens that are well tolerated and convenient Increased availability of viral load monitoring and resistance testing Use of viral load monitoring and viral resistance assays, if available

Implementation research on interventions to support adherence and on optimal options for monitoring of PLWH on ART Research on transmission risk in patients with undetectable plasma viral load

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Table 7 continued.

Achilles' Heel Challenges Potential Solutions

Acute HIV infection • Contribution to 5%-95% of new HIV • Development of inexpensive rapid point-of-care assays for acute infections HIV infection

• Lack of simple and inexpensive rapid tests for • Increased utilization of laboratory-based HIV testing through detection of acute HIV multiple platform analyzers

• Limited utilization of HIV testing through • Implementation research on interventions to increase provider multiple platform analyzers that detect early and population knowledge of signs and symptoms of acute HIV HIV infection infection

• Lack of clinical provider knowledge of acute • Implementation research on interventions to increase testing for HIV signs and symptoms and testing for its acute HIV infection by providers detection

• Lack of awareness by individuals of signs and symptoms of acute HIV infection

Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; PLWH, people living with HIV; WHO, World Health Organization.

alternative types of testing, and more often resulted in partner present to care. A study analyzing data from the HIV Outpatient

testing [38]. Study (HOPS) found that the baseline CD4+ count at entry into care among 1203 patients was 299 cells/pL and did not change

Linkage to Care substantially from 2001 to 2009 [47], In comparison, a study Gaps in linkage of PLWH from HIV testing to enrollment in from San Francisco of 3588 HIV-infected individuals aged HIV care has raised the concern that a "positive HIV test >13 years from 2004 to 2010 reported an increase in median often leads to nowhere" [39], In many HIV programs, data CD4+ count at diagnosis from 384 cells/pL in 2004 to 623 are not available on linkage to care due to lack of required re- cells/pL in 2010 [48]. porting for this parameter and the separate operations of testing In SSA, late entry into care remains a significant challenge,

and care services [29], Current rates of reported linkage vary with median CD4+ counts of 154-274 cells/pL in one meta

greatly, from 33% to 88% (median 59%) in SSA [40], In analysis [49]. In patients enrolling at HIV care programs in 9 New York City, 23% of HIV-infected patients identified in one SSA countries, the proportion that enrolled in care with CD4+

study had delayed entry to care >3 months after diagnosis [41], count <100 cells/pL or World Health Organization (WHO) In 2012, a panel recommended a target of 85% of newly diag- Stage 4 decreased from 19.8% to 15.6% (P< .001) from 2005 nosed individuals be linked to care within 3 months of testing in to 2010 with an increase in median CD4+ count at enrollment

the United States [42], in care from 254 cells/pL (interquartile range [IQR], 110-458) A review of 42 studies, the majority from South Africa, re- to 300 cells/pL (IQR, 139-500), respectively [50], Nonetheless,

ported that the most commonly cited barriers to linkage to further progress is needed to achieve earlier diagnosis of HIV

care were transport cost and distance from clinic, followed by infection and entry of such patients into continuity care stigma and clinic factors such as long waiting times [43], A re- promptly after diagnosis, cent systematic review of 14 studies examining interventions to

promote linkage to or utilization of care among HIV diagnosed ART Initiation

persons identified that active care coordination in helping or ac- Delayed ART initiation among eligible patients has been shown

companying clients to care, motivational counseling, and in- to be associated with high mortality. In a study of 1235 treat

creased education about linkage may be helpful in improving ment-naive ART-eligible adults in South Africa, mortality linkage to care [44]. Innovative strategies to improve linkage rates were 33.3 deaths per 100 person-years in the pretreatment

that have shown promising effects include point-of-care CD4+ interval as compared to 19.1 deaths and 2.9 deaths per 100 per

testing [45] and case managers [46]. son-years in the first 4 months of ART and after 4 months of ART, respectively [51]. More than 84% of deaths occurred

Enrollment in Care at Advanced Stages of HIV Disease prior to ART initiation or during the first 4 months, indicating Late enrollment in care at advanced HIV disease stages jeopar- the need for earlier initiation of ART.

dizes individuals' ability to garner the benefits of earlier diagno- Although ART initiation among eligible patients has in sis, treatment, and disease management for their own health, as creased in both developed and developing countries, many pa

well as missed opportunities for prevention of HIV transmis- tients are still initiating ART late with CD4+ counts below sion to others. This may be due to late diagnosis of HIV infec- recommended guidelines. In one US cohort, ART initiation in tion or failure of those who are aware of HIV infection to creased from 51% in 2001 to 72% in 2009 (P for trend <.001) in

1006 • CID 2014:58 (1 April) • HIV/AIDS

Achilles' Heel Challenges Potential Solutions

Acute HIV infection • Contribution to 5%-95% of new HIV • Development of inexpensive rapid point-of-care assays for acute infections HIV infection

• Lack of simple and inexpensive rapid tests for • Increased utilization of laboratory-based HIV testing through detection of acute HIV multiple platform analyzers

• Limited utilization of HIV testing through • Implementation research on interventions to increase provider multiple platform analyzers that detect early and population knowledge of signs and symptoms of acute HIV HIV infection infection

• Lack of clinical provider knowledge of acute • Implementation research on interventions to increase testing for HIV signs and symptoms and testing for its acute HIV infection by providers detection

• Lack of awareness by individuals of signs and symptoms of acute HIV infection

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one US cohort [52]. In a study that assessed initiation of ART confidence limit of 1.27 per 100 person-years [62], An estimated

in 9 countries from sub-Saharan Africa, the proportion of HIV- 19%—25% of PLWH in the United States had viral load suppres

infected adults who initiated ART late with CD4+ count <100 sion [33,63-65], More recently, it has been estimated that 32%

cells/pL or WHO Stage 4 decreased from 43.3% in 2005 to of PLWH were virologically suppressed in British Columbia,

30.6% (P < .001) in 2010 with an increase in median CD4+ 52% of PLWH in Seattle, Washington, and 50% of PLWH in count at ART initiation from 125 cells/pL (IQR, 56-198 ) to France [66-68], but even these estimates may not sufficiently 178 cells/pL (IQR, 110-458) during this time period [50]. To decrease HIV transmission [18].

improve this further, efforts are needed to increase HIV testing, An important potential risk of unsuppressed viral load is the

linkage to care, and stigma reduction [53], development of HIV resistance [69, 70], Early use of ART for High rates of acceptance of ART initiation are also important the purpose of prevention poses the challenge of lifelong adher

to achieve the promise of ART for prevention. In a study of ence for many years, particularly as these individuals are likely

newly diagnosed individuals in South Africa who were eligible to be asymptomatic, a group in which adherence may be more

for ART, 20% refused referral to initiate treatment, of whom limited [71]. HIV drug resistance in SSA is increasing [72,73],

92% continued to refuse after 2 months of counseling [54]. and the ability to detect resistant strains and access to second

The leading reason for refusal was "feeling healthy." In addi- and third-line regimens are limited, factors which may limit the

tion, of 850 participants randomized to the delayed ART initi- impact of treatment for prevention [72]. ation arm of HPTN 052 who were offered ART after the For individuals who achieve undetectable viral load in the

release of the randomized portion of the study results, 19% de- plasma, recent data suggest that some have detectable virus in

clined ART for reasons of not feeling ready (37%), believing semen and genital tract secretions in men and women, respec

their CD4 was too high (28%), still deciding (9%), and other tively, which could potentially pose transmission risk despite

reasons [55]. high adherence to ART.

Retention in Care Detection of Acute and Early HIV Infection

Retention in care has been cited as a critical challenge for HIV For HIV treatment to be effective for prevention, identification

programs. Retention is poorer among patients enrolled in HIV °f as many individuals as possible with HIV infection is re

care who have yet to initiate ART as compared to patients who quired. Studies estimate the proportion of HIV infections attrib

have initiated ART [56-58]. Evidence also indicates poorer re- utable to acute or early HIV infection to be between 5% and

tention in patients with higher CD4+ counts, a finding of par- 95% [74]. In a study from Malawi, an estimate of 38% of HIV

ticular importance as at the core of the concept of ART for transmission was attributable to sexual contact with an individ

prevention is the intent to initiate ART in asymptomatic indi- ua' w'^ acute infection [75]. The absence of simple and afford -

viduals with early HIV disease. In a study from Rwanda that in- able tests that detect acute infection, however, poses an

eluded 18 955 adult patients who enrolled in care from 2004 to important challenge. Two studies that evaluated the point-of

2011, retention was highest among those with lower CD4+ care Determine HIV-1/2 Ag/Ab Combo test, which includes

counts and more advanced HIV disease stage in both patients p24 Ag testing, in Malawi and Swaziland demonstrated the fail

in care and those on ART [59]. In a study from South Africa of ure of this test to detect acute infection [76,77]. To date, the US

4223 HIV-infected individuals not yet eligible for ART, reten- Food and Drug Administration has approved 2 laboratory tion at 1 year by initial CD4+ count was lowest among those based fourth-generation HIV diagnostic tests that are able to de

with higher CD4+ count [60]. Overall, it is estimated that tect early acute HIV [78]. 25%-33% of HIV-infected persons have initiated ART [40, 49],

with less than three-quarters retained in care 1 year after ART ART COVERAGE SHOULD BE THE initiation [61]. OVERARCHING GOAL

Viral Load Suppression Perhaps the most important measure that will determine the Viral load suppression in PLWH is required for optimal indi- potential for ART for prevention is the extent of ART coverage

vidual health outcomes and for the concept of ART for preven- for PLWH within a community. ART coverage has significantly

tion. It is important to note that viral load measurement is not increased in low- and middle-income countries from 47% in

routinely available in SSA; thus, data on viral load suppression 2010 to 54% in 2011 based on 2010 WHO treatment threshold

are limited from such settings. In a meta-analysis of 11 studies guidelines that included CD4+ count <350 cells/pL and/or

of ART for prevention in serodiscordant couples, the rate of WHO Stage 3 or 4 [79]. In developing countries, ART coverage

HIV transmission from a seropositive partner with viral load has rapidly expanded, with some countries such as Rwanda and

<400 copies/mL on ART was zero with an upper 97.5% Botswana achieving >80% ART coverage among eligible adults

HIV/AIDS • CID 2014:58 (1 April) • 1007

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as per 2010 WHO guidelines [31]. However, other countries such as Nigeria and Angola have yet to achieve 30% coverage

rates [80]. A study from US HIV clinics reported a 9% increase

in ART coverage in eligible adults from 74% in 2000 to 83% in

2008 [81]. The effect of the recent changes in WHO guidelines

on ART coverage will be important to monitor [82].

To increase ART coverage to those who need treatment for

their own health and beyond for the purpose of prevention,

there is a critical need to focus on components of the health

system including task shifting to increase nonphysician HIV

providers [83,84], an increase in ART access through decentral

ization of HIV care to primary health centers, consistency of

drug supply and laboratory tests, an increase in demand for

HIV testing, care, and treatment and availability of supportive

services to PLWH and a supportive community [85, 86].

RESEARCH QUESTIONS

There is a paucity of data on the efficacy of ART for prevention

in key populations such as MSM, persons who inject drugs, and

sex workers —populations that contribute a substantial propor

tion of new HIV infections in various settings [87-90]. Ecolog

ical data provide support of effect of ART expansion on number

of new infections in injection drug users in Vancouver and Bal

timore [15, 91, 92], whereas a modeling study of MSM in the

United Kingdom demonstrated a rise in HIV incidence despite

high coverage of ART and only a modest increase in condom less sex [93].

Initiation of ART in individuals with early HIV disease poses

unique challenges, particularly with regard to demand genera

tion, enhancing acceptability of ART initiation, and adherence

with treatment for the long term. In addition, the balance of

risks vs benefits of early ART for such individuals remains un

clear [94]. Observational studies have shown conflicting results

with regard to this balance, particularly in terms of effect on

mortality, and were solely conducted in resource-rich settings

[93], Ongoing studies such as the Strategic Timing of Antiretro

viral Treatment (START) study are evaluating the risk and ben

efit of early ART for individuals with CD4+ count >500 cells/pL,

largely in high- and middle-income settings [95], Further re search is needed to evaluate the individual risk-benefits in re

source-limited settings [94].

There is also the need for evidence-based implementation

science studies on the "how"—how to improve the performance

of the health system as related to all the elements of the HIV care continuum. Such studies should aim to evaluate a combi

nation strategy that includes interventions targeted for various

steps in the HIV care cascade and its effect on population out

comes for both treatment and prevention. In terms of determin

ing the effectiveness of ART for prevention, 2 studies are

planned to address this question, the HPTN (PopART) study

to be conducted in South Africa and another study to take

place in Botswana [96, 97].

CONCLUSIONS

The promise of ART for prevention has stimulated great opti

mism in confronting the HIV epidemic. However, for this

promise to be fully realized, attention must be given to existing

vulnerabilities, or Achilles' heel, which threaten this potential.

Attention to relevant health system elements and improvements

in each step of the HIV care continuum, from testing to long

term medication adherence, need to be achieved. Most impor

tantly, respecting individual autonomy and patient preferences

and desires are of paramount importance as expansion of use of

ART for prevention is considered.

Notes

Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases through the HIV Prevention Trials Net work (grant number UM1 AI068619 to W. E. S.).

Potential conflicts of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the con

tent of the manuscript have been disclosed.

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