Articles tagged as "HIV testing and treatment"

Couples learning from couples: now is the time to test together

Evaluation of a demand-creation intervention for couples' HIV testing services among married or cohabiting individuals in Rakai, Uganda: a cluster-randomized intervention trial.

Matovu JK, Todd J, Wanyenze RK, Kairania R, Serwadda D, Wabwire-Mangen F. BMC Infect Dis. 2016 Aug 8;16:379. doi: 10.1186/s12879-016-1720-y.

Background: Uptake of couples' HIV counseling and testing (couples' HCT) services remains largely low in most settings. We report the effect of a demand-creation intervention trial on couples' HCT uptake among married or cohabiting individuals who had never received couples' HCT.

Methods: This was a cluster-randomized intervention trial implemented in three study regions with differing HIV prevalence levels (range: 9-43 %) in Rakai district, southwestern Uganda, between February and September 2014. We randomly assigned six clusters (1:1) to receive the intervention or serve as the comparison arm using computer-generated random numbers. In the intervention clusters, individuals attended small group, couple and male-focused interactive sessions, reinforced with testimonies from 'expert couples', and received invitation coupons to test together with their partners at designated health facilities. In the comparison clusters, participants attended general adult health education sessions but received no invitation coupons. The primary outcome was couples' HCT uptake, measured 12 months post-baseline. Baseline data were collected between November 2013 and February 2014 while follow-up data were collected between March and April 2015. We conducted intention-to-treat analysis using a mixed effects Poisson regression model to assess for differences in couples' HCT uptake between the intervention and comparison clusters. Data analysis was conducted using STATA statistical software, version 14.1.

Results: Of 2135 married or cohabiting individuals interviewed at baseline, 42% (n = 846) had ever received couples' HCT. Of those who had never received couples' HCT (n = 1174), 697 were interviewed in the intervention clusters while 477 were interviewed in the comparison clusters. 73.6% (n = 513) of those interviewed in the intervention and 82.6% (n = 394) of those interviewed in the comparison cluster were interviewed at follow-up. Of those interviewed, 72.3% (n = 371) in the intervention and 65.2% (n = 257) in the comparison clusters received HCT. Couples' HCT uptake was higher in the intervention than in the comparison clusters (20.3% versus 13.7%; adjusted prevalence ratio (aPR) = 1.43, 95% CI: 1.02, 2.01, P = 0.04).

Conclusion: Our findings show that a small group, couple and male-focused, demand-creation intervention reinforced with testimonies from 'expert couples', improved uptake of couples' HCT in this rural setting.

Trial registration: ClinicalTrials.gov, NCT02492061. Date of registration: June 14, 2015.

Abstract  Full-text [free] access

Editor’s notes: Effective programmes to increase HIV testing uptake are necessary, given new guidance from WHO recommending an immediate offer of antiretroviral therapy (ART) to all people who test HIV-positive regardless of CD4 count. This HIV testing demand creation trial involving married or cohabiting couples residing in Rakai, Uganda sheds light on strategies for achieving 90% knowledge of HIV-positive serostatus among all people living with HIV. In reality, HIV-serodiscordant couples have a striking 50% HIV prevalence from their partnership. Knowledge of serostatus is therefore critical to preventing HIV transmission to the HIV-negative partner and to an offspring. Such knowledge is also the doorway to early initiation of ART with its proven clinical benefits for the HIV-positive partner and reduced risk of HIV transmission to the HIV-negative partner. This intervention trial contributes to the literature on couples’ testing uptake generated through studies in Rwanda and Zambia in which influential network agents invited couples to take up HIV testing and counselling together. This trial was conducted in a highly studied population that has undergone annual sero-surveillance for over 20 years. At baseline 94.6% of individuals interviewed had already had an HIV test, 42% had a history of previous couples’ HIV testing and counselling (HTC), and 62.3% had had tested for HIV in the past year. People who had never received couples’ HTC formed the study populations. Couples in the programme clusters participated in couple- and male-focused demand creation small groups in which ‘expert couples’ shared their couple testing experiences. It is not possible to know which components of this relatively expensive programme were most effective. Uptake of couples HTC was modest at 20.3% compared with 13.7% in the control arm. Since this trial was conducted, new promising technologies have come on the horizon, including self-testing and point of care testing. Combining these with concerted efforts to reduce stigma and discrimination while increasing access to ART should see steady increases in uptake of couples’ HCT. Further, there is enough evidence now to suggest that engaging men and encouraging couple-to-couple conversations about testing can influence couples’ decisions to have an HIV test.

Africa
Uganda
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Poor linkage to care may undermine benefits of universal test and treat

Uptake of home-based HIV testing, linkage to care, and community attitudes about ART in rural KwaZulu-Natal, South Africa: descriptive results from the first phase of the ANRS 12249 TasP cluster-randomised trial.

Iwuji CC, Orne-Gliemann J, Larmarange J, Okesola N, Tanser F, Thiebaut R, Rekacewicz C, Newell ML, Dabis F. PLoS Med. 2016 Aug 9;13(8):e1002107. doi: 10.1371/journal.pmed.1002107. eCollection 2016.

Background: The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu-Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART.

Methods and findings: Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count ≤ 350 cells/µl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (≥16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded. In all, 12 894 adults were registered as eligible for participation (5790 in intervention arm; 7104 in control arm), of whom 9927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8233/9927 (82.9%), including 2569 ascertained as HIV-positive (942 tested HIV-positive and 1627 reported a known HIV-positive status). Of the 1177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count ≤350 cells/µl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8802/9460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2028/6656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count ≤350 cells/µl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded.

Conclusions: Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV-positive people accessed care within 6 mo of being identified, with nearly two-thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population.

Trial registration: ClinicalTrials.gov NCT01509508.

Abstract  Full-text [free] access 

Editor’s notes: The UNAIDS treatment target set for 2020 aim for at least 90 percent of all people living with HIV to be diagnosed, at least 90 percent of people diagnosed to receive antiretroviral therapy, and for treatment to be effective and consistent enough in at least 90 percent of people on treatment to suppress the virus. This would result in about 73% of all HIV-positive people being virally suppressed. 

This paper describes the key process indicators (such as uptake of initial and repeat home-based HIV testing, linkage to care, uptake of ART, and viral suppression) along the treatment cascade during the two-year initial phase of a trial evaluating a treatment as prevention package in a rural South African setting. Although the investigators were unable to contact one-quarter of the potential key population - especially men - they found good acceptance of home-based HIV testing.

However, they found disappointingly low rates of linkage to care. Only about half of HIV-positive participants not yet in care attended a clinic within six months of diagnosis. This increased to two-thirds after 12 months, partly due the efforts of a linkage-to-care team. They contacted those not linked to care three months after an HIV-positive test. Among people who did present to the clinics, the rates of ART uptake, retention in care and viral suppression were high.

The main study (reported at the AIDS 2016 conference in Durban) did not demonstrate an effect of offering immediate ART on HIV incidence at population level, mainly due the low rates of linkage to care following HIV diagnosis. 

These results suggest that systems to improve linkage to care will be necessary if the individual and public health benefits of universal testing and treatment are to be maximised.

Africa
South Africa
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HIV treatment during acute infection can lead to false negative HIV antibody tests

Initiation of antiretroviral therapy during acute HIV-1 infection leads to a high rate of nonreactive HIV serology.

de Souza MS, Pinyakorn S, Akapirat S, Pattanachaiwit S, Fletcher JL, Chomchey N, Kroon ED, Ubolyam S, Michael NL, Robb ML, Phanuphak P, Kim JH, Phanuphak N, Ananworanich J. Clin Infect Dis. 2016 Aug 15;63(4):555-61. doi: 10.1093/cid/ciw365. Epub 2016 Jun 17.

Background: Third- and fourth-generation immunoassays (IAs) are widely used in the diagnosis of human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) during acute HIV infection (AHI) may impact HIV-specific antibodies, with failure to develop antibody or seroreversion. We report on the ability of diagnostic tests to detect HIV-specific antibodies in Thai participants initiating ART during AHI.

Methods: Participants with detectable plasma HIV RNA but nonreactive HIV-specific immunoglobulin G, enrolled in an AHI study, were offered immediate initiation of ART. Participants were tested at initiation and at 12 and 24 weeks following treatment using standard second-, third-, and fourth-generation IAs and Western blot (WB).

Results: Participants (N = 234) initiating ART at a median of 19 days (range, 1-62 days) from HIV exposure demonstrated different frequencies of reactivity prior to and following 24 weeks of ART depending on the IA. Third-generation IA nonreactivity prior to ART was 48%, which decreased to 4% following ART (P < .001). Fourth-generation IA nonreactivity was 18% prior to ART and 17% following ART (P = .720). Negative WB results were observed in 89% and 12% of participants prior to and following 24 weeks of ART, respectively (P < .001). Seroreversion to nonreactivity during ART was observed to at least one of the tests in 20% of participants, with fourth-generation IA demonstrating the highest frequency (11%) of seroreversion.

Conclusions: HIV-specific antibodies may fail to develop and, when detected, may decline when ART is initiated during AHI. Although fourth-generation IA was the most sensitive at detecting AHI prior to ART, third-generation IA was the most sensitive during treatment.

Clinical trials registration: NCT00796146 and NCT00796263.

Abstract access  

Editor’s notes: Antibodies to HIV become detectable around three weeks after HIV infection. Fourth generation HIV tests detect both HIV antibodies and the p24 HIV antigen, and can therefore detect HIV infection earlier than second and third-generation tests, which are based on detection of antibodies. Fourth generation tests therefore allow for earlier initiation of antiretroviral therapy (ART) relative to second- and third-generation HIV tests.

There have been sporadic reports of seroreversion from being HIV antibody positive to negative, or failure to seroconvert to being HIV antibody positive, following initiation of ART, particularly from paediatric populations. This study examined the impact of ART initiation during acute HIV infection on HIV diagnostic test results. Although the fourth-generation HIV test was the most sensitive at detecting acute HIV infection, it also had the highest frequency of seroreversion. Conversely, third generation HIV tests were positive prior to the start of ART in just over half of participants, compared to nearly all by 12 weeks after ART initiation. Notably, the Western blot, which was historically used as a confirmatory test for HIV, had high rates of non-reactivity in acute infection and 12% of tests were negative at 24 weeks after treatment, demonstrating that this test is not informative as a confirmatory assay in the context of acutely-treated HIV infection.   

The recent WHO guidelines recommend ART for all HIV-positive people regardless of age and disease stage.  Initiating ART as early as possible following HIV infection has also been recommended as a means to limit the size of the viral reservoir and improve prognosis. It is therefore likely that increasing numbers of individuals will start ART during early infection. There may be instances where individuals on ART may retest either due to doubts about results, or when they relocate to other HIV services. Clinicians need to be aware of the possibility of false-negative HIV antibody tests among people taking ART, particularly among individuals who initiated treatment during acute infection.    

Asia
Thailand
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Access improved to HIV testing through peer administered oral fluid HIV tests in key populations in Brazil

Point-of-care HIV tests done by peers, Brazil.

Pascom AR, Dutra de Barros CH, Lobo TD, Pasini EN, Comparini RA, Caldas de Mesquita F. Bull World Health Organ. 2016 Aug 1; 94(8): 626–630.

Problem: Early diagnosis of infections with human immunodeficiency virus (HIV) is needed - especially among key populations such as sex workers, transgender people, men who have sex with men and people who use drugs.

Approach: The Brazilian Ministry of Health developed a strategy called Viva Melhor Sabendo ("live better knowing") to increase HIV testing among key populations. In partnership with nongovernmental organizations (NGOs), a peer point-of-care testing intervention, using an oral fluid rapid test, was introduced at social venues for key populations at different times of the day.

Local setting: Key populations in Brazil can have 40 times higher HIV prevalence than the general population (14.8% versus 0.4%).

Relevant changes: Legislation was reinterpreted, so that oral fluid rapid tests could be administered by any person trained in rapid testing by the health ministry. Between January 2014 and March 2015, 29 723 oral fluid tests were administered; 791 (2.7%) were positive. Among the key populations, transgender people had the greatest proportion of positive results (10.7%; 172/1612), followed by men who declared themselves as commercial sex workers (8.7%; 165/1889) and men who have sex with men (4.8%; 292/6055).

Lessons learnt: The strategy improved access to HIV testing. Testing done by peers at times and locations suitable for key populations increased acceptance of testing. Working with relevant NGOs is a useful approach when reaching out to these key populations.

Abstract  Full-text [free] access 

Editor’s notes: Brazil was a pioneer in provision of universal access to ART, adopting universal treatment for all people living with HIV in 2013. The HIV epidemic in Brazil is largely concentrated in key populations, where early treatment is less likely to be initiated than in the general population. In this report, the authors describe the results of a new strategy to allow trained peers from 53 non-governmental organisations (NGOs) to conduct rapid HIV screening tests using oral fluid tests, and refer clients with positive results for treatment. Key features were the full ownership of the testing implementation by the NGOs, extension of testing to social venues, and the matching of testers and clients by demographic characteristics. About half of the clients (53%) were first-time testers, providing clear evidence of the success of this new strategy. Future work should describe how individual NGOs revised their strategy over time, which NGOs were more successful in reaching key populations, and which NGOs were more successful in referring clients with positive results for test confirmation and treatment.

Latin America
Brazil
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Systematic review finds that the evidence for the impact of HCT on HIV acquisition is limited but scale-up remains vital to facilitate other proven interventions

The effect of HIV counselling and testing on HIV acquisition in sub-Saharan Africa: a systematic review.

Rosenberg NE, Hauser BM, Ryan J, Miller WC. Sex Transm Infect. 2016 Aug 16. pii: sextrans-2016-052651. doi: 10.1136/sextrans-2016-052651. [Epub ahead of print]

Objectives: Annually, millions of people in sub-Saharan Africa (SSA) receive HIV counselling and testing (HCT), a service designed to inform persons of their HIV status and, if HIV uninfected, reduce HIV acquisition risk. However, the impact of HCT on HIV acquisition has not been systematically evaluated. We conducted a systematic review to assess this relationship in SSA.

Methods: We searched for articles from SSA meeting the following criteria: an HIV-uninfected population, HCT as an exposure, longitudinal design and an HIV acquisition endpoint. Three sets of comparisons were assessed and divided into strata: sites receiving HCT versus sites not receiving HCT (Strata A), persons receiving HCT versus persons not receiving HCT (Strata B) and persons receiving couple HCT (cHCT) versus persons receiving individual HCT (Strata C).

Results: We reviewed 1635 abstracts; eight met all inclusion criteria. Strata A consisted of one cluster randomised trial with a non-significant trend towards HCT being harmful: incidence rate ratio (IRR): 1.4. Strata B consisted of five observational studies with non-significant unadjusted IRRs from 0.6 to 1.3. Strata C consisted of two studies. Both displayed trends towards cHCT being more protective than individual HCT (IRRs: 0.3-0.5). All studies had at least one design limitation.

Conclusions: In spite of intensive scale-up of HCT in SSA, few well-designed studies have assessed the prevention impacts of HCT. The limited body of evidence suggests that individual HCT does not have a consistent impact on HIV acquisition, and cHCT is more protective than individual HCT.

Abstract access  

Editor’s notes: Although it is plausible that knowing that you are HIV-negative might be an incentive for safer behaviour and thus reduce the risk of HIV acquisition, previous studies have not been conclusive.  HIV counselling and testing (HCT) is an integral part of other prevention and treatment activities (e.g. voluntary medical male circumcision (VMMC) or pre-exposure prophylaxis (PreP)). The findings from this systematic review suggest that with the available evidence individual HCT does not consistently have a protective or harmful effect on HIV acquisition. Couples’ HCT may be protective but the authors caution against a simplistic interpretation, reminding us of limited evidence including imprecise estimates and possibilities of bias. There were just two studies on couples’ HCT and convincing evidence of benefit was only seen in the study which compared couples’ HCT with individual HCT. There could be systematic differences between people who sought couples’ versus individual HCT (who may be unable or unwilling to take up a couples programme). While couples’ HCT may be suited to some people and be protective for them, the wider applicability may be more limited. The authors describe the methodological challenges of measuring the impact of an HCT activity on HIV acquisition, including the fact that large cohorts need to be effectively followed for long periods. In addition, randomised comparisons with no HCT are not possible because of ethical barriers to withholding HCT. Another challenge the authors cite is that both the primary exposure (HCT) and the primary outcome (HIV acquisition) require an HIV test. Arguably, this could be circumvented by offering anonymised remote (eg laboratory) HIV testing to determine HIV acquisition, rather than point-of-care tests where results would be immediately available. The final message from this paper is that although convincing evidence for reduction in HIV acquisition from HCT is not apparent, it’s scale-up must continue. HCT is the gateway to other proven activities for both prevention and treatment.

HIV testing
Africa
Rwanda, South Africa, Uganda, Zimbabwe
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Mental health as a barrier to HIV testing and care

Pathways to HIV testing and care in Goa, India: exploring psychosocial barriers and facilitators using mixed methods.

Mayston R, Lazarus A, Patel V, Abas M, Korgaonkar P, Paranjape R, Rodrigues S, Prince M. BMC Public Health. 2016 Aug 11;16(1):765. doi: 10.1186/s12889-016-3456-4.

Background: Despite recognition of the importance of timely presentation to HIV care, research on pathways to care is lacking. The adverse impact of depression upon adherence to antiretroviral therapy is established. There is emerging evidence to suggest depression may inhibit initial engagement with care. However, the effect of depression and other psychosocial factors upon the pathway to care is unknown.

Methods: We used mixed methods to explore pathways to care of people accessing testing and treatment in Goa, India. Questionnaires including measures of common mental disorder, hazardous alcohol use, cognition and assessment of pathways to care (motivations for testing, time since they were first aware of this reason for testing, whether they had been advised to test, who had given this advice, time elapsed since this advice was given) were administered to 1934 participants at the time of HIV testing. Qualitative interviews were carried out with 15 study participants who attended the antiretroviral therapy treatment centre. Interview topic guides were designed to elicit responses that discussed barriers and facilitators of accessing testing and care.

Results: Pathways were often long and complex. Quantitative findings revealed that Common Mental Disorder was associated with delayed testing when advised by a Doctor (the most common pathway to testing) (AOR = 6.18, 2.16-17.70). Qualitative results showed that triggers for testing (symptoms believed to be due to HIV, and for women, illness or death of their husband) suggested that poor health, rather than awareness of risk was a key stimulus for testing. The period immediately before and after diagnosis was characterised by distress and fear. Stigma was a prominent backdrop to narratives. However, once participants had made contact with care and support (HIV services and non-governmental organisations), these systems were often effective in alleviating fear and promoting confidence in treatment and self-efficacy.

Conclusion: The effectiveness of formal and informal systems of support around the time of diagnosis in supporting people with mental disorder is unclear. Ways of enhancing these systems should be explored, with the aim of achieving timely presentation at HIV care for all those diagnosed with the disease.

Abstract  Full-text [free] access 

Editor’s notes: Late presentation to HIV care is associated with poorer outcomes for individuals living with HIV (increased risk of morbidity and death) and for treatment programmes (increased costs). The focus of this mixed methods study was to improve understanding of the impact of common mental disorders, hazardous alcohol use and cognitive impairment on accessing HIV testing and care in India. Although the investigators report that common mental disorders increased the possibility of delayed testing, internalised stigma and fear of discrimination was a common theme in the qualitative narratives. Stigma is associated with poorer mental health, including emotional distress, depression and reduced psychological functioning. It has also been linked to intermediate health outcomes such as seeking healthcare and adherence to antiretroviral therapy. These results reinforce the need to develop and evaluate programmes to address HIV-associated stigma so that people living with HIV can access care and benefit from treatment. However, development of appropriate programmes requires a better understanding of the complexities of HIV-associated stigma. These include the relationship between stigma, depression and social support and the intersection of HIV-associated stigma and other types of stigma experienced by people living with HIV, such as homophobia and gender discrimination.

Asia
India
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South Africa’s major cascade gap is between testing and treatment

Level of viral suppression and the cascade of HIV care in a South African semi-urban setting in 2012.

Jean K, Puren A, Cutler E, Singh B, Bouscaillou J, Rain-Taljaard R, Taljaard D, Gouws E, Lissouba P, Lewis DA, Peytavin G, Auvert B. AIDS. 2016 Aug 24;30(13):2107-16. doi: 10.1097/QAD.0000000000001155.

Objective: In 2012, 7 years after the introduction of antiretroviral treatment (ART) in the South African township of Orange Farm, we measured the proportion of HIV-positive people who were virally suppressed, especially among high-risk groups (women 18-29 years and men 25-34 years).

Design: A community-based cross-sectional representative survey was conducted among 3293 men and 3473 women.

Methods: Study procedures included a face-to-face interview and collection of blood samples that were tested for HIV, 11 antiretroviral drugs and HIV-viral load.

Results: HIV prevalence was 17.0% [95% confidence interval: 15.7-18.3%] among men and 30.1% [28.5-31.6%] among women. Overall, 59.1% [57.4-60.8%] of men and 79.5% [78.2-80.9%] of women had previously been tested for HIV. When controlling for age, circumcised men were more likely to have been tested compared with uncircumcised men (66.1 vs 53.6%; P < 0.001). Among HIV+, 21.0% [17.7-24.6%] of men and 30.5% [27.7-33.3%] of women tested positive for one or more antiretroviral drugs. Using basic calculations, we estimated that, between 2005 and 2012, ART programs prevented between 46 and 63% of AIDS-related deaths in the community. Among antiretroviral-positive, 91.9% [88.7-94.3%] had viral suppression (viral load <400 copies/ml). The proportion of viral suppression among HIV+ was 27.0% [24.3-29.9%] among women and 17.5% [14.4-20.9%] among men. These proportions were lower among the high-risk groups: 15.6% [12.1-19.7%] among women and 8.4% [5.0-13.1%] among men.

Conclusion: In Orange Farm, between 2005 and 2012, ART programs were suboptimal and, among those living with HIV, the proportion with viral suppression was still low, especially among the young age groups. However, our study showed that, in reality, antiretroviral drugs are highly effective in viral suppression at an individual level.

Abstract access  

Editor’s notes: The efficacy of antiretroviral treatment (ART) in preventing HIV transmission from HIV-positive to HIV-negative people is clearly established. However, HIV incidence remains stubbornly high in many settings, and the challenge is to find ways to implement ART at sufficient scale, in combination with other effective programmes, to make an impact on HIV incidence at community level.

In this study, the authors surveyed a representative sample of adults in a community near Johannesburg, South Africa, where HIV prevalence is high and ART has been widely available since 2005. A trial of voluntary male medical circumcision (VMMC) was run in this location between 2002 to 2004, and a programme of incentivised VMMC and community mobilisation have been in place since 2008. The proportion of adults who had ever tested for HIV was nearly 80% among women and 60% among men, similar to that reported at national level in South Africa. Among survey participants with detectable ART agents in their blood, 94% had an HIV viral load below 1000 copies per ml, 92% below 400 copies per ml and 78% below 50 copies per ml. However, because ART programmes were sub-optimal at the time of the study, only 24% of all HIV-positive people in the survey had an HIV viral load below 400 copies per ml.

This study presents data from a real-world setting in South Africa. During the time of the study (2005-2012) treatment programmes were still sub-optimal (using the WHO 2006 treatment guidelines) but it shows that for all people on ART, significant levels of viral suppression were obtained. Of critical importance for treatment programmes will be to make sure that people have access to testing services and that testing and treatment programmes are linked. 

Africa
South Africa
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Antiretroviral therapy dramatically reduces transmission of HIV to sexual partners

Antiretroviral therapy for the prevention of HIV-1 transmission.

Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Cottle L, Zhang XC, Makhema J, Mills LA, Panchia R, Faesen S, Eron J, Gallant J, Havlir D, Swindells S, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano DD, Essex M, Hudelson SE, Redd AD, Fleming TR. N Engl J Med. 2016 Jul 18. [Epub ahead of print]

Background: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.

Methods: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis.

Results: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.

Conclusions: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Abstract access

Editor’s notes: The HPTN 052 trial has been a landmark study in establishing antiretroviral therapy as a strategy for preventing onward transmission of HIV. It was a study of more than 800 couples. More than half of the couples were in African countries. In each couple, one sexual partner was HIV positive and the other HIV negative.  The participants living with HIV were randomised either to receive immediate antiretroviral therapy or to delay until their CD4 count fell to 350, an approved approach at that time. The HIV negative partners were then monitored for acquisition of HIV.  When new HIV infections occurred, the virus was studied for genetic similarity to the virus of the known positive partner. The interim analysis was published in 2011.  It illustrated the programme to be so effective that the randomisation was ended and all the participants living with HIV were offered antiretroviral therapy. 

This article presents data after five years of follow-up, and if anything the results are even more remarkable. In more than 10 000 person-years of follow up, there were only eight transmissions of genetically linked virus from participants receiving antiretroviral therapy. Of these transmissions, four occurred early in treatment when the viral load would not be expected to be suppressed.  The other four occurred after treatment failure. In this enormous study, there were therefore no linked transmissions from participants who were stable on treatment without detectable viraemia. The study provides powerful support for the UNAIDS 90-90-90 treatment target.  The widest possible effective use of antiretroviral therapy will not only improve the health of people treated but could have a dramatic effect on new HIV infections.

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Weekend breaks on efavirenz-based ART non-inferior in adolescents

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.

Butler K, Inshaw J, Ford D, Bernays S, Scott K, Kenny J, Klein N, Turkova A, Harper L, Nastouli E, Paparini S, Choudhury R, Rhodes T, Babiker A, Gibb D. Health Technol Assess. 2016 Jun;20(49):1-108. doi: 10.3310/hta20490.

Background: For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings.

Objectives: To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy.

Design: Open, randomised, non-inferiority trial.

Setting: Europe, Thailand, Uganda, Argentina and the USA.

Participants: Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months.

Interventions: Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART).

Main outcome measures: Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age.

Results: In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm3, respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial.

Conclusions: Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned.

Trial registration: Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.

Abstract  Full-text [free] access 

Editor’s notes: Adherence to ART has been shown to deteriorate in adolescence, with missed doses occurring particularly at weekends. Pharmacokinetic properties of some ART drugs, such as efavirenz, allow for a break in pill taking without a break in effective treatment. Non-inferiority trials evaluating five days on, two days off in adults have shown continuous ART to be non-inferior with low rates of virologic rebound.  This formed the rationale for this global, randomised Phase II/III trial in young people.

In the BREATHER trial, non-inferiority of viral suppression in adolescents on efavirenz-based first-line ART was shown for short-cycle treatment compared with continuous treatment. Overall 93% of adolescents remained virally suppressed. Findings from the two-year long-term follow-up phase will confirm if short-cycle treatment is effective and safe in this population.  Further studies are required to confirm the applicability of this strategy in real-life settings where viral load monitoring is likely to be less frequent than in a trial setting.

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HIV-exposed uninfected children – why the increased mortality risk?

HIV-exposed children account for more than half of 24-month mortality in Botswana.

Zash R, Souda S, Leidner J, Ribaudo H, Binda K, Moyo S, Powis KM, Petlo C, Mmalane M, Makhema J, Essex M, Lockman S, Shapiro R. BMC Pediatr. 2016 Jul 21;16:103. doi: 10.1186/s12887-016-0635-5.

Background: The contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined.

Methods: From January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1-3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling.

Results: Three thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58% received three-drug ART, 23% received zidovudine alone, 11% received no antiretrovirals (8% unknown); 2.1% of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5%) children; 106 (3.5%) died including 12 (38%) HIV-infected, 70 (4.7%) HIV-exposed uninfected, and 24 (1.6%) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95% CI 10.7, 47.5), child HIV-exposure (aHR 2.7, 95% CI 1.7, 4.5) and maternal death (aHR 8.9, 95% CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95% CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26% maternal HIV prevalence), an estimated 52% of child mortality occurs among HIV-exposed or HIV-infected children.

Conclusions: In a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children.

Abstract  Full-text [free] access 

Editor’s notes: It has been known for some time that HIV-exposed but uninfected children have a higher risk of death than HIV-unexposed children. There is now a need for prospective studies to explore the mechanisms underlying this observation. In this study from Botswana, one of every 20 HIV-exposed but uninfected children had died by 24 months. Four in every five deaths in the HIV-exposed but uninfected children were attributed to infectious diseases, most commonly diarrhoeal illness and respiratory infections.

The analysis was unfortunately not able to unpick the effect of infant feeding on mortality in the HIV-exposed uninfected children. Only 16% of HIV-exposed children were breastfed. This is consistent with national guidelines at the time, where formula feeding was recommended for mothers living with HIV. It is reassuring that in recently updated national guidelines, exclusive breastfeeding for six months is now recommended for mothers living with HIV on ART with virologic suppression.

Mother-to-child HIV transmission at 24 months was still around 2%, and further infections may have been undiagnosed in children who died before being tested. More than one in three children living with HIV died within 24 months. This reminds us that while there is increasing interest in HIV-exposed uninfected children, our priority for now should still be achieving elimination of mother-to-child HIV transmission.

Africa
Botswana
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