Articles tagged as "Biomedical interventions and prevention tools"

Intimate partner violence is a challenge to PrEP adherence

Intimate partner violence and adherence to HIV pre-exposure prophylaxis (PrEP) in African women in HIV serodiscordant relationships: a prospective cohort study.

Roberts ST, Haberer J, Celum C, Mugo N, Ware NC, Cohen CR, Tappero JW, Kiarie J, Ronald A, Mujugira A, Tumwesigye E, Were E, Irungu E, Baeten JM. J Acquir Immune Defic Syndr. 2016 May 26. [Epub ahead of print]

Background: Intimate partner violence (IPV) is associated with higher HIV incidence, reduced condom use, and poor adherence to antiretroviral therapy and other medications. IPV may also affect adherence to pre-exposure prophylaxis (PrEP).

Methods: We analyzed data from 1785 HIV-uninfected women enrolled in a clinical trial of PrEP among African HIV-serodiscordant couples. Experience of verbal, physical, or economic IPV was assessed at monthly visits by face-to-face interviews. Low PrEP adherence was defined as clinic-based pill count coverage <80% or plasma tenofovir levels <40 ng/mL. The association between IPV and low adherence was analyzed using generalized estimating equations, adjusting for potential confounders. In-depth interview transcripts were examined to explain how IPV could impact adherence.

Results: 16% of women reported IPV during a median of 34.8 months of follow-up (IQR 27.0 - 35.0). Overall, 7% of visits had pill count coverage <80% and 32% had plasma tenofovir <40 ng/mL. Women reporting IPV in the past 3 months had increased risk of low adherence by pill count (adjusted RR 1.49, 95% CI 1.17-1.89) and by plasma tenofovir (adjusted RR 1.51, 95% CI 1.06-2.15). Verbal, economic, and physical IPV were all associated with low adherence. However, the impact of IPV diminished and was not statistically significant 3 months after the reported exposure. In qualitative interviews, women identified several ways in which IPV affected adherence, including stress and forgetting, leaving home without pills, and partners throwing pills away.

Conclusion: Women who reported recent IPV in the Partners PrEP Study were at increased risk of low PrEP adherence. Strategies to mitigate PrEP non-adherence in the context of IPV should be evaluated.

Abstract access

Editor’s notes: The high rates of HIV infection in women underscore persistent gender inequalities, in particular that of violence against women. Intimate partner violence (IPV) puts women at increased risk of HIV infection. Further, among women living with HIV, IPV has also been associated with lower rates of treatment uptake and adherence to antiretroviral therapy (ART). The interaction between IPV and HIV is complex, and includes biological, socio-economic and cultural mechanisms. This is the first study to examine the association between IPV and adherence to HIV pre-exposure prophylaxis (PrEP).  Women who had experienced IPV in the past three months were 50% more likely than women who had never experienced IPV to have poor adherence, as measured by both pills counts and drug levels in the blood.  Recent IPV was also associated with an increase in the risk of HIV infection.  Women in the study were in stable, serodiscordant relationships, had enrolled in the study together with their partners, and were using PrEP with their partner’s consent. The proportion of women reporting IPV during the study was much lower than national estimates in the region.  These findings are thus of concern for PrEP demonstration projects focusing on key populations at high risk of HIV, who may experience higher rates of IPV and be less likely to have partner support. 

PrEP is a key element of combination HIV prevention strategies in high-risk populations, but requires high adherence in order to be effective. Programmes focusing on promoting PrEP adherence in women who have experienced violence are urgently needed.  More broadly, HIV prevention programmes should be expanded to integrate IPV prevention as an important component to reducing women’s risk of HIV.

Kenya, Uganda
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Circumcising young adults: a higher return on investment

Effectiveness of and financial returns to voluntary medical male circumcision for HIV prevention in South Africa: an incremental cost-effectiveness analysis.

Haacker M, Fraser-Hurt N, Gorgens M. PLoS Med. 2016 May 3;13(5):e1002012. doi: 10.1371/journal.pmed.1002012. eCollection 2016.

Background: Empirical studies and population-level policy simulations show the importance of voluntary medical male circumcision (VMMC) in generalized epidemics. This paper complements available scenario-based studies (projecting costs and outcomes over some policy period, typically spanning decades) by adopting an incremental approach-analyzing the expected consequences of circumcising one male individual with specific characteristics in a specific year. This approach yields more precise estimates of VMMC's cost-effectiveness and identifies the outcomes of current investments in VMMC (e.g., within a fiscal budget period) rather than of investments spread over the entire policy period.

Methods/findings: The model has three components. We adapted the ASSA2008 model, a demographic and epidemiological model of the HIV epidemic in South Africa, to analyze the impact of one VMMC on HIV incidence over time and across the population. A costing module tracked the costs of VMMC and the resulting financial savings owing to reduced HIV incidence over time. Then, we used several financial indicators to assess the cost-effectiveness of and financial return on investments in VMMC. One circumcision of a young man up to age 20 prevents on average over 0.2 HIV infections, but this effect declines steeply with age, e.g., to 0.08 by age 30. Net financial savings from one VMMC at age 20 are estimated at US$617 at a discount rate of 5% and are lower for circumcisions both at younger ages (because the savings occur later and are discounted more) and at older ages (because male circumcision becomes less effective). Investments in male circumcision carry a financial rate of return of up to 14.5% (for circumcisions at age 20). The cost of a male circumcision is refinanced fastest, after 13 y, for circumcisions at ages 20 to 25. Principal limitations of the analysis arise from the long time (decades) over which the effects of VMMC unfold-the results are therefore sensitive to the discount rate applied, and more generally to the future course of the epidemic and of HIV/AIDS-related policies pursued by the government.

Conclusions: VMMC in South Africa is highly effective in reducing both HIV incidence and the financial costs of the HIV response. The return on investment is highest if males are circumcised between ages 20 and 25, but this return on investment declines steeply with age.

Abstract  Full-text [free] access 

Editor’s notes: Voluntary medical male circumcision is known to be an effective HIV-infection prevention method. While many models and papers have explored the cost and cost-effectiveness of voluntary medical male circumcision at a population level, the authors carry out their analysis using an incremental approach, looking at the expected consequences of circumcising one male individual within a specific year. Their findings are consistent with previous work on the topic, namely that voluntary medical male circumcision is highly effective in countries with high HIV prevalence and is, under many circumstances, cost-saving. They also find that voluntary medical male circumcision is most effective when performed at age 20, and effectiveness declines at higher ages due to diminished direct and indirect effects on HIV incidence.

While it would indeed be wise for countries to consider long-term impacts of programmes, governments often make decisions in the short-term. It is therefore important for governments to understand the benefits of a programme or policy that are accrued during the timeframe of presidential or congressional terms. The findings and the approach used in this study are very important because they present evidence of impact of investment within a government’s current budget process. By providing a way to measure the immediate return on investment, the authors of this paper help inform policymakers in a way that is tangible, pragmatic, and, unfortunately, not often used.  

South Africa
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Injectable PrEP, if targeted well, could be good value for money

Cost-effectiveness of injectable preexposure prophylaxis for HIV prevention in South Africa.

Glaubius RL, Hood G, Penrose KJ, Parikh UM, Mellors JW, Bendavid E, Abbas UL. Clin Infect Dis. 2016 May 18. pii: ciw321. [Epub ahead of print]

Background: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for HIV prevention. However, the cost-effectiveness of injectable PrEP is unclear.

Methods: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios, over ten-year and lifetime horizons, assuming a societal perspective.

Results: Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over ten years. HIV prevention doubled (17%) when the same coverage was prioritized to 20-29 year-old women, costing $10 880-$19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing $298-$1242 per infection prevented. Over lifetime, PrEP scale-up among 20-29 year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk-prioritization was cost-saving. PrEP's ten-year impact decreased by almost 50% with increases in incremental cost-effectiveness ratios (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy and reliability of delivery, as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy.

Conclusions: Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.

Abstract access

Editor’s notes: Pre-exposure prophylaxis (PrEP) has been shown to work when people are able to use it well.  But recent trials have illustrated that people are not always able to take tablets or use vaginal gels frequently enough to maximise protection. A promising area in HIV prevention research is long-lasting injectable PrEP, which would only require application once every month or so. This paper estimates whether injectable PrEP might be cost effective in South Africa.  The authors explore how this form of PrEP should be targeted to different groups. Injectable PrEP is estimated to be very cost-effective in general, and would save money if people at highest risk were able to gain access. However, because an injectable product has not been fully developed yet, this analysis requires many assumptions. The authors test how changes in these assumptions might give a different conclusion. They find that the most important factors are the cost of injectable PrEP products themselves, how well they work, and whether they can be made available to people who need them.

South Africa
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Finding out at home: community members’ and healthcare workers’ views on the use of oral HIV self-testing in Kayelitsha, South Africa

'I know that I do have HIV but nobody saw me': oral HIV self-testing in an informal settlement in South Africa.

Martinez Perez G, Cox V, Ellman T, Moore A, Patten G, Shroufi A, Stinson K, Van Cutsem G, Ibeto M. PLoS One. 2016 Apr 4;11(4):e0152653. doi: 10.1371/journal.pone.0152653. eCollection 2016.

Reaching universal HIV-status awareness is crucial to ensure all HIV-infected patients access antiretroviral treatment (ART) and achieve virological suppression. Opportunities for HIV testing could be enhanced by offering self-testing in populations that fear stigma and discrimination when accessing conventional HIV Counselling and Testing (HCT) in health care facilities. This qualitative research aims to examine the feasibility and acceptability of unsupervised oral self-testing for home use in an informal settlement of South Africa. Eleven in-depth interviews, two couple interviews, and two focus group discussions were conducted with seven healthcare workers and thirteen community members. Thematic analysis was done concurrently with data collection. Acceptability to offer home self-testing was demonstrated in this research. Home self-testing might help this population overcome barriers to accepting HCT; this was particularly expressed in the male and youth groups. Nevertheless, pilot interventions must provide evidence of potential harm related to home self-testing, intensify efforts to offer quality counselling, and ensure linkage to HIV/ART-care following a positive self-test result.

 Abstract Full-text [free] access

Editor’s notes: This is a qualitative study with services users and healthcare workers from an HIV testing service ran by Médecins Sans Frontières (MSF) in Kayelitsha, South Africa. Couple and individual interviews and focus group discussions were conducted with 20 people. The participants discussed preferences of types of HIV testing and acceptability of HIV home-testing. The aim was to inform the pilot of an activity for the use of an oral HIV self-testing device (OraQuick). OraQuick is self-administered as an oral swab and gives results straightaway. The study sample included people who had previously refused an HIV test in the clinic, people who had received an HIV test in the clinic and agreed to a couple interview with their partners. Key reasons for refusing an HIV test in the clinic included: fear of finding out one’s status, fear of HIV-treated discrimination and concerns about confidentiality in testing services. Clinics were seen by male participants as ‘women’s places’.  Men thought visiting a service for an HIV test could harm one’s reputation. Home-testing was seen as preferable because it afforded more privacy. However, not wanting to know one’s status remains a barrier even with home-testing. There were concerns that partners (of both sexes) could pressure one another to test with OraQuick and tensions could arise in case of serodiscordant results. There were concerns that some users could get confused by a test that detects the presence of HIV in the mouth. This would contradict current awareness that HIV cannot be passed through kissing. False-negative tests could encourage unsafe sex. Participants worried that some people may not link into care and treatment after finding out they are HIV positive with a home-test. The study concludes that home-testing could reach populations (especially male partners of women living with HIV and young people) that do not come forward for testing through other services, including clinic-based and voluntary community testing. Many of the disadvantages of home-testing could be mitigated with appropriate education and pre-test counselling. The pilot study continues.  It is expected that the study will be able to address questions of linkage to care for people who test HIV-positive. 

South Africa
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Comparing the performance of different community-based measures of viral load as correlates for HIV incidence

Community viral load, antiretroviral therapy coverage, and HIV incidence in India: a cross-sectional, comparative study.

Solomon SS, Mehta SH, McFall AM, Srikrishnan AK, Saravanan S, Laeyendecker O, Balakrishnan P, Celentano DD, Solomon S, Lucas GM. Lancet HIV. 2016 Apr;3(4):e183-90. doi: 10.1016/S2352-3018(16)00019-9. Epub 2016 Mar 11.

Background: HIV incidence is the best measure of treatment-programme effectiveness, but its measurement is difficult and expensive. The concept of community viral load as a modifiable driver of new HIV infections has attracted substantial attention. We set out to compare several measures of community viral load and antiretroviral therapy (ART) coverage as correlates of HIV incidence in high-risk populations.

Methods: We analysed data from a sample of people who inject drugs and men who have sex with men, who were participants of the baseline assessment of a cluster-randomised trial in progress across 22 cities in India ( number NCT01686750). We recruited the study population by use of respondent-driven sampling and did the baseline assessment at 27 community-based sites (12 for men who have sex with men and 15 for people who inject drugs). We estimated HIV incidence with a multiassay algorithm and calculated five community-based measures of HIV control: mean log10 HIV RNA in participants with HIV in a community either engaged in care (in-care viral load), aware of their status but not necessarily in care (aware viral load), or all HIV-positive individuals whether they were aware, in care, or not (population viral load); participants with HIV in a community with HIV RNA more than 150 copies per mL (prevalence of viraemia); and the proportion of participants with HIV who self-reported ART use in the previous 30 days (population ART coverage). All participants were tested for HIV, with additional testing in HIV-positive individuals. We assessed correlations between the measures and HIV incidence with Spearman correlation coefficients and linear regression analysis.

Findings: Between Oct 1, 2012, and Dec 19, 2013, we recruited 26 503 participants, 12 022 men who have sex with men and 14 481 people who inject drugs. Median incidence of HIV was 0.87% (IQR 0.40-1.17) in men who have sex with men and 1.43% (0.60-4.00) in people who inject drugs. Prevalence of viraemia was more strongly correlated with HIV incidence (correlation 0.81, 95% CI 0.62-0.91; p<0.0001) than all other measures, although correlation was significant with aware viral load (0.59, 0.27-0.79; p=0.001), population viral load (0.51, 0.16-0.74; p=0.007), and population ART coverage (-0.54, -0.76 to -0.20; p=0.004). In-care viral load was not correlated with HIV incidence (0.29, -0.10 to 0.60; p=0.14). With regression analysis, we estimated that to reduce HIV incidence by 1 percentage point in a community, prevalence of viraemia would need to be reduced by 4.34%, and ART use in HIV-positive individuals would need to increase by 19.5%.

Interpretation: Prevalence of viraemia had the strongest correlation with HIV incidence in this sample and might be a useful measure of the effectiveness of a treatment programme.

Abstract access    

Editor’s notes: The ideal metric of impact for a programme looking at the prevention benefits of treatment would be the reduction in HIV incidence in the target population. Incidence is however very difficult to measure. ‘Community viral load’ has been proposed as an alternative. However its estimation using data collected either in a routine clinical setting or from a cohort study can suffer from bias, due to the population included not being representative of the wider population of people living with HIV.

This paper describes a study among gay men and other men who have sex with men and people who inject drugs carried out at 27 sites in India. Participants were recruited using respondent-driven sampling (in which respondents recruit their peers to produce a generally representative sample of hard-to-reach populations). At each site incidence was estimated using a multi-assay algorithm designed to identify seroconversion occurring approximately within the last six months. Five community-based measures of viral load were measured at each site. Of these, the prevalence of HIV viraemia (i.e. the proportion of the population with a viral load greater than 150 copies per mL), was most strongly associated with HIV incidence, while mean viral load among people in-care was not associated. This latter finding is important if a case-based surveillance approach using only data collected at clinics is to be used to estimate incidence. Population ART coverage, a measure of the proportion of the site participants on ART was also strongly correlated with incidence. As this can be measured through a simple questionnaire, rather than lab-based assays, it could be an easily and cheaply obtainable correlate for incidence, albeit one potentially prone to response bias.

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Stopping PrEP use due to changes in partnership dynamics and life events could increase HIV risk

When and why women might suspend PrEP use according to perceived seasons of risk: implications for PrEP-specific risk-reduction counselling.

Namey E, Agot K, Ahmed K, Odhiambo J, Skhosana J, Guest G, Corneli A. Cult Health Sex. 2016 Apr 19:1-11. [Epub ahead of print]

Oral pre-exposure prophylaxis (PrEP) using the antiretroviral drug emtricitabine/tenofovir disoproxil fumarate (Truvada) has been shown to dramatically reduce the risk of HIV acquisition for women at higher risk of infection if taken daily. Understanding when and why women would intentionally stop using an efficacious oral PrEP drug within the context of their 'normal' daily lives is essential for delivering effective PrEP risk-reduction counselling. As part of a larger study, we conducted 60 qualitative interviews with women at higher risk of HIV in Bondo, Kenya, and Pretoria, South Africa. Participants charted their sexual contacts over the previous six months, indicated whether they would have taken PrEP if available and discussed whether and why they would have suspended PrEP use. Nearly all participants said they would have used PrEP in the previous six months; half indicated they would have suspended PrEP use at some point. Participants' reasons for an extended break from PrEP were related to partnership dynamics (e.g., perceived low risk of a stable partner) and phases of life (e.g., trying to conceive). Life events (e.g., holidays and travel) could prompt shorter breaks in PrEP use. These circumstances may or may not correspond to actual contexts of lower risk, highlighting the importance of tailored PrEP risk-reduction counselling.

 Abstract access 

Editor’s notes: This paper presents findings from a qualitative study that aimed to understand why and when women would stop using oral PrEP in the context of their everyday lives. The study included 30 semi-structured interviews with women in Kenya and 30 with women in South Africa.  All were participants in a larger study exploring PrEP and risk compensation who were HIV negative (aged between 18 and 35 years).

The authors found that nearly all women would have taken PrEP six months before the interview. Reasons for stopping PrEP use due to partnership dynamics included the absence of a partner, the end of a relationship, infrequent sex, marriage and stable or faithful relationships. Phases of life which would stop women using PrEP included trying to conceive, pregnancy and older age.  Life events such as illness, stressful events, travelling and festivals affected PrEP use.

The authors provided a number of suggestions for counsellors to support women to assess risk and need to use PrEP. This could include information on the HIV-infection risk due to the difficulty of negotiating condom use. The authors also suggested the use of couples counselling and male engagement strategies. The authors recommended that counsellors should counsel that risk may increase during travel and holidays. Such suggestions highlight the usefulness of this study in understanding why women would stop PrEP use.

Kenya, South Africa
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The dapivirine ring confers moderate efficacy, but hope for a new prevention option

Use of a vaginal ring containing dapivirine for HIV-1 prevention in women.

Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, Mgodi NM, Matovu Kiweewa F, Nair G, Mhlanga F, Siva S, Bekker LG, Jeenarain N, Gaffoor Z, Martinson F, Makanani B, Pather A, Naidoo L, Husnik M, Richardson BA, Parikh UM, Mellors JW, Marzinke MA, Hendrix CW, van der Straten A, Ramjee G, Chirenje ZM, Nakabiito C, Taha TE, Jones J, Mayo A, Scheckter R, Berthiaume J, Livant E, Jacobson C, Ndase P, White R, Patterson K, Germuga D, Galaska B, Bunge K, Singh D, Szydlo DW, Montgomery ET, Mensch BS, Torjesen K, Grossman CI, Chakhtoura N, Nel A, Rosenberg Z, McGowan I, Hillier S, Team M-AS N Engl J Med. 2016 Feb 22. [Epub ahead of print]

Background: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection.

Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe.

Results: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.05) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups.

Conclusions: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence.

 Abstract  Full-text [free] access 

Editor’s notes: Women bear a larger proportion of the HIV burden worldwide due to biological and behavioural factors. As a result, the HIV prevention field has focused research over the past couple of decades to identify new prevention options especially for women, to reduce this burden. The study presented in this paper is the first to publish phase III efficacy trial results for a vaginal ring containing the antiretroviral drug dapivirine for HIV prevention. The ring is designed to prevent HIV acquisition locally within the vagina in HIV negative women and kept in the body for a period of four weeks. This strategy is meant to address two components of adherence and side effects. A longer-acting product and local application is contrasted with the daily and systemic use of oral pre-exposure prophylaxis, a regimen which can be difficult to maintain. This study found that the dapivirine ring did not protect women with a high rate of efficacy, 27% overall. Interestingly, the sub-analyses of the data illustrated that there was better protection in women with better adherence, and in women who were over the age of 21. Further explorations of the data along with the qualitative findings from the study will surely provide more valuable insights into the low overall rate of efficacy, and perhaps most importantly into why age made such a difference in rates of protection. As mentioned in the paper, a second study on the ring, which was presented at CROI 2016, publishing similar results, and those results combined with the data from this study will further our knowledge regarding the viability of this HIV prevention option.  

Malawi, South Africa, Uganda, Zimbabwe
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Couples talking about prevention and supporting each other on PrEP and ART: lessons from Kenya

I knew I would be safer. Experiences of Kenyan HIV serodiscordant couples soon after pre-exposure prophylaxis (PrEP) initiation.

Ngure K, Heffron R, Curran K, Vusha S, Ngutu M, Mugo N, Celum C, Baeten JM. AIDS Patient Care STDS. 2016 Feb;30(2):78-83. doi: 10.1089/apc.2015.0259.

Pre-exposure prophylaxis (PrEP) for HIV-uninfected persons is highly efficacious for HIV prevention. Understanding how people at risk for HIV will use PrEP is important to inform PrEP scale-up and implementation. We used qualitative methods to gather insights into couples' early experiences with PrEP use within the Partners Demonstration Project, an open-label implementation study evaluating integrated delivery of PrEP and antiretroviral therapy (ART). PrEP is offered to HIV uninfected partners until the HIV-infected partner initiates and sustains ART use (i.e., PrEP as a "bridge" to ART initiation and viral suppression). From August 2013 to March 2014 we conducted 20 in-depth dyadic interviews (n = 40) with heterosexual HIV serodiscordant couples participating at the Thika, Kenya study site, exploring how couples make decisions about using PrEP for HIV prevention. We developed and applied deductive and inductive codes to identify key themes related to experiences of PrEP initiation and use of time-limited PrEP. Couples reported that PrEP offered them an additional strategy to reduce the risk of HIV transmission, meet their fertility desires, and cope with HIV serodiscordance. Remaining HIV negative at follow-up visits reinforced couples' decisions and motivated continued adherence to PrEP. In addition, confidence in their provider's advice and client-friendly services were critical to their decisions to initiate and continue use of PrEP. Strategies for wide-scale PrEP delivery for HIV serodiscordant couples in low resource settings may include building capacity of health providers to counsel on PrEP adoption while addressing couples' concerns and barriers to adoption and continued use.

Abstract access

Editor’s notes: This paper is based on findings from the Partners Demonstration Project. This project evaluated the implementation of ART and PrEP for HIV-1 prevention in African heterosexual HIV-1 serodiscordant couples in Uganda and Kenya. As has been reported elsewhere, the research achieved impressive reductions in HIV-incidence. The strategy adopted in the project was to provide PrEP to the HIV-negative partner until the HIV-positive partner had sustained their use of ART for six months. Using data from Kenya, the authors describe in this paper the value placed by couples on PrEP, which underpinned the study success. Couples wanted to use PrEP because PrEP (and ART) provided the possibility of reduced HIV transmission. In addition to the findings on reasons for PrEP use, this paper also offers insights into couple dynamics. The research was conducted with mutually disclosed HIV serodiscordant couples. The authors illustrated through their analysis and the excerpts from interviews used in the text, the importance of communication between partners. They also, importantly, illustrate differences between couples. The authors describe the use of both verbal and non-verbal communication in discussions about PrEP and ART. Through the data in this paper a picture is built up on the importance of open and frank communication in decisions about using and sustaining the use of PrEP and ART. In a study setting, couples could be afforded support which might be scarce in public health settings. Even so, the findings underline the value of being sensitive to context and individual needs, in supporting PrEP and ART roll-out.

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Novel specimens feasible and sensitive for Xpert® MTB/RIF diagnosis in children

Performance of Xpert® MTB/RIF and alternative specimen collection methods for the diagnosis of tuberculosis in HIV-infected children.

Marcy O, Ung V, Goyet S, Borand L, Msellati P, Tejiokem M, Nguyen Thi NL, Nacro B, Cheng S, Eyangoh S, Pham TH, Ouedraogo AS, Tarantola A, Godreuil S, Blanche S, Delacourt C, PAANTHER study group. Clin Infect Dis. 2016 Feb 7. pii: ciw036. [Epub ahead of print]

Methods: HIV-infected children aged 13 years with suspected intrathoracic tuberculosis were enrolled in 8 hospitals in Burkina Faso, Cambodia, Cameroon, and Vietnam. Gastric aspirates were taken for children aged <10 years and expectorated sputum samples were taken for children aged 10 years (standard samples); nasopharyngeal aspirate and stool were taken for all children, and a string test was performed if the child was aged 4 years (alternative samples). All samples were tested with Xpert®. The diagnostic accuracy of Xpert® for culture-confirmed tuberculosis was analyzed in intention-to-diagnose and per-protocol approaches.

Results: Of 281 children enrolled, 272 (96.8%) had ≥1 specimen tested with Xpert® (intention-to-diagnose population), and 179 (63.5%) had all samples tested with Xpert® (per-protocol population). Tuberculosis was culture-confirmed in 29/272 (10.7%) children. Intention-to-diagnose sensitivities of Xpert® performed on all, standard, and alternative samples were 79.3% (95% confidence interval [CI], 60.3-92.0), 72.4% (95% CI, 52.8-87.3), and 75.9% (95% CI, 56.5-89.7), respectively. Specificities were 97.5%. Xpert® combined on nasopharyngeal aspirate and stool had intention-to-diagnose and per-protocol sensitivities of 75.9% (95% CI, 56.5-89.7) and 75.0% (95% CI, 47.6-92.7), respectively.

Conclusions: The combination of nasopharyngeal aspirate and stool sample is a promising alternative to methods usually recommended by national programs. Xpert® performed on respiratory and stools samples enables rapid confirmation of tuberculosis diagnosis in HIV-infected children.

Abstract access  

Editor’s notes: This article reports on a prospective cohort study of HIV-positive children (≤ 13 years) with suspected intrathoracic tuberculosis in eight hospitals in Burkina Faso, Cambodia, Cameroon, and Viet Nam. Diagnosis of tuberculosis among children is challenging because it is more difficult to obtain sputum, and their sputum often has fewer bacilli, requiring more sensitive tests. In 2014, WHO recommended scaling-up the use of Xpert® MTB/RIF among children. However, any test which is dependent on obtaining a sputum specimen will be suboptimal for diagnosis of tuberculosis in children.

In this study the investigators examined the feasibility of using alternative specimens with Xpert® MTB/ RIF for the diagnosis of tuberculosis in HIV-positive children. Using an intention-to-diagnose and a per-protocol analysis, they also assessed the diagnostic accuracy of Xpert® on nasopharyngeal aspirate and stool samples, using culture-confirmed tuberculosis as the reference standard.

The authors found that the performance of Xpert® in alternative samples was comparable to that of standard samples. They found excellent feasibility of obtaining samples of nasopharyngeal aspirates and stool, and a good sensitivity of Xpert® (~76%) when using that combination of samples. The authors suggested more research to simplify the processing of the stool samples for Xpert®, which would make the combination of both samples an attractive collection method for children unable to produce sputum.

Although Xpert® produces results relatively rapidly, some testing was done retrospectively, and only half of the Xpert® results were immediately available. As many children in this study had features of severe disease, it is not surprising that clinicians often started TB treatment immediately without waiting for results. Thus in practice the Xpert® result often provided bacteriological confirmation of a clinical diagnosis for children who had already started TB treatment, although it did also lead to some TB treatment initiations.

Despite conducting this study over more than two years in eight hospitals, the final number of enrolled children with culture-confirmed tuberculosis was only 29. It would be interesting to know whether using Xpert® on alternative specimens from children had an impact on patient-important outcomes, particularly mortality, though this would have required a much larger study. Studies of Xpert® implementation among adults have found increased yield in terms of bacteriological diagnoses. However, most have not found an impact on patient-important outcomes. Several children died before all the protocol-required specimens could be obtained, emphasizing the importance of rapid and more sensitive TB diagnostic tests for severely-ill children.

Africa, Asia
Burkina Faso, Cambodia, Cameroon, Viet Nam
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Fewer deaths with empirical TB treatment among seriously ill people

Empiric TB treatment of severely ill patients with HIV and presumed pulmonary TB improves survival.

Katagira W, Walter ND, den Boon S, Kalema N, Ayakaka I, Vittinghoff E, Worodria W, Cattamanchi A, Huang L, Davis JL. J Acquir Immune Defic Syndr. 2016 Feb 24. [Epub ahead of print]

Rationale: In 2007, WHO issued emergency recommendations on empiric treatment of sputum acid-fast bacillus (AFB) smear-negative patients with possible tuberculosis (TB) in HIV-prevalent areas, and called for operational research to evaluate their effectiveness. We sought to determine if early, empiric TB treatment of possible TB patients with abnormal chest radiography or severe illness as suggested by the 2007 WHO guidelines is associated with improved survival.

Methods: We prospectively enrolled consecutive HIV-seropositive inpatients at Mulago Hospital in Kampala, Uganda, from 2007 to 2011 with cough 2 weeks. We retrospectively examined the effect of empiric TB treatment before discharge on eight-week survival among those with and without a WHO-defined 'danger sign,' including fever >39 degrees C, tachycardia >120 beats-per-minute, or tachypnea >30 breaths-per-minute. We modeled the interaction between empiric TB treatment and danger signs and their combined effect on eight-week survival and adjusted for relevant covariates.

Results: Among 631 sputum smear-negative patients, 322(51%) had danger signs. Cumulative eight-week survival of patients with danger signs was significantly higher with empiric TB treatment (80%) than without (64%, p<0.001). After adjusting for duration of cough and concurrent hypoxemia, patients with danger signs who received empiric TB treatment had a 44% reduction in eight-week mortality(Risk Ratio 0.54, 95%CI 0.32-0.91, p=0.020).

Conclusions: Empiric TB treatment of HIV-seropositive, smear-negative, presumed pulmonary TB patients with one or more danger signs is associated with improved eight-week survival. Enhanced implementation of the 2007 WHO empiric-treatment recommendations should be encouraged whenever and wherever rapid and highly sensitive diagnostic tests for TB are unavailable.

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Editor’s notes: TB remains the most important cause of death among people living with HIV worldwide. Empirical TB treatment, meaning treatment without bacteriological confirmation, is common practice among people with symptoms suggesting TB, where diagnostic tests are unsatisfactory and the risk of death is high if TB were left untreated.

WHO recommends empirical TB treatment for people living with HIV who are seriously ill, for example as indicated by one or more “danger signs” (respiratory rate over 30 per minute, temperature over 39ºC, pulse over 120, unable to walk unaided).  However the evidence to guide the use of empirical TB treatment is very limited. This study adds to that evidence base. HIV-positive adult in-patients with a cough of at least two weeks duration were recruited as part of a study of pneumonia, in a referral hospital in Uganda, and underwent a standard set of investigations. This sub-analysis included people who were sputum smear negative, and investigated the association of empirical TB treatment with survival at eight weeks. Among individuals who had one or more danger signs, people who were treated for TB were more likely to be alive at eight weeks (80% versus 64%). Among people without danger signs, mortality was not associated with empirical TB treatment (survival at eight weeks, 76% among people treated empirically versus 74% among people not treated).

It is important to keep in mind that this was an observational cohort, not a randomised trial, and the implementation of empirical TB treatment according to WHO guidelines was far from complete. Among HIV-positive adults eligible for the study (cough for at least two weeks and sputum smear negative), over half had one or more danger signs, but only 23% of them received TB treatment. Some 20% of the people included in the study were already taking antiretroviral therapy (ART). It is implied that few started ART during admission, and this may also have contributed to high mortality.

This study is particularly relevant in the context of the results of two recent trials of empirical TB treatment. One, the REMEMBER trial will be discussed in next month’s digest. Briefly this study found no mortality benefit of empirical TB treatment over isoniazid preventive therapy among HIV-positive people with CD4 counts below 50 among whom locally-available diagnostic tests had not detected TB. The other trial, TB Fast Track, was presented at CROI in February. This trial found no difference in mortality among adult out-patients, with CD4 counts of 150 or fewer. The patients were managed according to a nurse-led algorithm using point of-care tests to stratify TB risk. Immediate empirical TB treatment for people at highest risk was compared to standard management. The results of all these studies should lead to better definition of criteria for the use of empirical TB treatment. Ultimately, however, better tests for TB that can be used in primary care settings are urgently needed. 

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