Articles tagged as "Epidemiology"

Invasive cervical cancers preventable by HPV vaccines: a comparison of HIV-positive and negative women

Effect of HIV infection on human papillomavirus types causing invasive cervical cancer in Africa.

Clifford GM, de Vuyst H, Tenet V, Plummer M, Tully S, Franceschi S. J Acquir Immune Defic Syndr. 2016 Nov 1;73(3):332-339.

Objectives: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type.

Design: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa.

Method: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR).

Results: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV.

Conclusions: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Abstract access  

Editor’s notes: Invasive cervical cancer (ICC) is one of the most common cancers in low and middle income countries. In the African region the prevalence of both ICC and HIV are high. Compared to HIV-negative women, HIV-positive women are at increased risk of oncogenic high-risk (HR) human papillomavirus (HPV) incidence and persistence, and cervical lesion incidence and progression. Current HPV vaccines offer potential for cervical cancer prevention by targeting the HR-HPV types associated with ICC. Although there is no data yet available on HPV vaccine efficacy among HIV-positive persons, HPV vaccines have been reported to be safe and immunogenic in HIV-positive children, female adolescents and adults. 

This systematic review compared the HPV type distribution and the HPV vaccine type distribution in ICC biopsy and cervical cell specimens of 770 HIV-positive and 3846 HIV-negative women from 21 studies in 12 African countries.

The authors report that the fraction of ICC attributable to the HPV types included in the current bivalent (HPV16/18) and nonavalent (HPV16/18/31/33/45/52/58) vaccines was similar among HIV-positive and HIV-negative women (bivalent: 61.7% and 67.3%; nonavalent: 88.9% and 89.5%, respectively). However, a non-negligible proportion of ICC from both HIV-positive and HIV-negative women were infected with non-vaccine types in the absence of any of the vaccine types (7.0% and 7.9% of ICC from HIV-positive and HIV-negative women, respectively), and this was highest for HPV35.

These findings confirm that the currently available HPV vaccines could prevent a similar proportion of ICC cases in HIV-positive as in HIV-negative women. ICC remains an important co-morbidity among HIV-positive women even in the antiretroviral era. Given that HIV-positive women are at greater risk of HR-HPV persistence and cervical lesion incidence and faster progression to high-grade cervical lesions, primary prevention of HPV infection through vaccination could reduce HPV infection and HPV-associated disease in Africa. However, cervical cancer screening will continue to remain important for both HIV-positive and HIV-negative women as there remain a proportion of ICC cases that may not be preventable by currently available vaccines. 

Comorbidity, Epidemiology
Africa
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School-based HIV prevention programmes appear ineffective

School-based interventions for preventing HIV, sexually transmitted infections, and pregnancy in adolescents.

Mason-Jones AJ, Sinclair D, Mathews C, Kagee A, Hillman A, Lombard C. Cochrane Database Syst Rev. 2016 Nov 8;11:CD006417.

Background: School-based sexual and reproductive health programmes are widely accepted as an approach to reducing high-risk sexual behaviour among adolescents. Many studies and systematic reviews have concentrated on measuring effects on knowledge or self-reported behaviour rather than biological outcomes, such as pregnancy or prevalence of sexually transmitted infections (STIs).

Objectives: To evaluate the effects of school-based sexual and reproductive health programmes on sexually transmitted infections (such as HIV, herpes simplex virus, and syphilis), and pregnancy among adolescents.

Search methods: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for published peer-reviewed journal articles; and ClinicalTrials.gov and the World Health Organization's (WHO) International Clinical Trials Registry Platform for prospective trials; AIDS Education and Global Information System (AEGIS) and National Library of Medicine (NLM) gateway for conference presentations; and the Centers for Disease Control and Prevention (CDC), UNAIDS, the WHO and the National Health Service (NHS) centre for Reviews and Dissemination (CRD) websites from 1990 to 7 April 2016. We hand searched the reference lists of all relevant papers.

Selection criteria: We included randomized controlled trials (RCTs), both individually randomized and cluster-randomized, that evaluated school-based programmes aimed at improving the sexual and reproductive health of adolescents.

Data collection and analysis: Two review authors independently assessed trials for inclusion, evaluated risk of bias, and extracted data. When appropriate, we obtained summary measures of treatment effect through a random-effects meta-analysis and we reported them using risk ratios (RR) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach.

Main results: We included eight cluster-RCTs that enrolled 55,157 participants. Five trials were conducted in sub-Saharan Africa (Malawi, South Africa, Tanzania, Zimbabwe, and Kenya), one in Latin America (Chile), and two in Europe (England and Scotland). Sexual and reproductive health educational programmes. Six trials evaluated school-based educational interventions. In these trials, the educational programmes evaluated had no demonstrable effect on the prevalence of HIV (RR 1.03, 95% CI 0.80 to 1.32, three trials; 14 163 participants; low certainty evidence), or other STIs (herpes simplex virus prevalence: RR 1.04, 95% CI 0.94 to 1.15; three trials, 17 445 participants; moderate certainty evidence; syphilis prevalence: RR 0.81, 95% CI 0.47 to 1.39; one trial, 6977 participants; low certainty evidence). There was also no apparent effect on the number of young women who were pregnant at the end of the trial (RR 0.99, 95% CI 0.84 to 1.16; three trials, 8280 participants; moderate certainty evidence). Material or monetary incentive-based programmes to promote school attendance. Two trials evaluated incentive-based programmes to promote school attendance. In these two trials, the incentives used had no demonstrable effect on HIV prevalence (RR 1.23, 95% CI 0.51 to 2.96; two trials, 3805 participants; low certainty evidence). Compared to controls, the prevalence of herpes simplex virus infection was lower in young women receiving a monthly cash incentive to stay in school (RR 0.30, 95% CI 0.11 to 0.85), but not in young people given free school uniforms (data not pooled, two trials, 7229 participants; very low certainty evidence). One trial evaluated the effects on syphilis and the prevalence was too low to detect or exclude effects confidently (RR 0.41, 95% CI 0.05 to 3.27; one trial, 1291 participants; very low certainty evidence). However, the number of young women who were pregnant at the end of the trial was lower among those who received incentives (RR 0.76, 95% CI 0.58 to 0.99; two trials, 4200 participants; low certainty evidence). Combined educational and incentive-based programmes. The single trial that evaluated free school uniforms also included a trial arm in which participants received both uniforms and a programme of sexual and reproductive education. In this trial arm herpes simplex virus infection was reduced (RR 0.82, 95% CI 0.68 to 0.99; one trial, 5899 participants; low certainty evidence), predominantly in young women, but no effect was detected for HIV or pregnancy (low certainty evidence).

Authors' conclusions: There is a continued need to provide health services to adolescents that include contraceptive choices and condoms and that involve them in the design of services. Schools may be a good place in which to provide these services. There is little evidence that educational curriculum-based programmes alone are effective in improving sexual and reproductive health outcomes for adolescents. Incentive-based interventions that focus on keeping young people in secondary school may reduce adolescent pregnancy but further trials are needed to confirm this.

Abstract  Full-text [free] access 

Editor’s notes: School-based HIV prevention programmes are widespread worldwide. These programmes use educational institutions as a venue to reach a population that is entering sexual maturity. Several systematic reviews have found beneficial effects of these programmes on HIV-associated knowledge and behaviours, though a subsequent effect of reduced HIV incidence remains unconfirmed. In this systematic review and meta-analysis, the authors included eight randomized controlled trials from sub-Saharan Africa, Europe, and Latin America. Whether using a curriculum- or incentive-based programme, the trials did not provide evidence of an effect of school-based programmes on reducing HIV infection. Nor was there compelling evidence of an effect of these programmes on reducing sexually transmitted infection or pregnancy. This paper highlights the difficulty of translating knowledge and reported behaviors into reductions in HIV infection and other biological outcomes. Further thought is necessary to deliver effective sexual and reproductive health programmes in schools – possibly including incentives, which show some promise but need further evidence on effectiveness. 

Africa, Europe, Latin America
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Longitudinal HIV viral load measures give insights into disease burden and transmission risk in the USA

Durable viral suppression and transmission risk potential among persons with diagnosed HIV infection: United States, 2012-2013.

Crepaz N, Tang T, Marks G, Mugavero MJ, Espinoza L, Hall HI. Clin Infect Dis. 2016 Oct 1;63(7):976-83. doi: 10.1093/cid/ciw418. Epub 2016 Jun 29.

Background: We examined durable viral suppression, cumulative viral load (VL) burden, and transmission risk potential among human immunodeficiency virus (HIV)-diagnosed persons in care.

Methods: Using data from the National HIV Surveillance System from 17 jurisdictions with complete reporting of VL test results, we determined the percentage of persons in HIV care who achieved durable viral suppression (all VL results <200 copies/mL) and examined viremia copy-years and time spent above VL levels that increase the risk of HIV transmission during 2012-2013.

Results: Of 265 264 persons in HIV care in 2011, 238 641 had at least 2 VLs in 2012-2013. The median number of VLs per individual during the 2-year period was 5. Approximately 62% had durable viral suppression. The remaining 38% had high VL burden (geometric mean of viremia copy-years, 7261) and spent an average of 438 days, 316 days, and 215 days (60%, 43.2%, and 29.5% of the 2-year period) above 200, 1500, and 10 000 copies/mL. Women, blacks/African Americans, Hispanics/Latinos, persons with HIV infection attributed to transmission other than male-to-male sexual contact, younger age groups, and persons with gaps in care had higher viral burden and transmission risk potential.

Conclusions: Two-thirds of persons in HIV care had durable viral suppression during a 2-year period. One-third had high VL burden and spent substantial time above VL levels with increased risk of onward transmission. More intervention efforts are needed to improve retention in care and medication adherence so that more persons in HIV care achieve durable viral suppression.

Abstract access  

Editor’s notes: Virologic suppression is the ultimate goal of HIV care. It determines health outcomes and transmission risk. Most analyses assess viral suppression by considering a single viral load measure. However, adherence to antiretroviral therapy and engagement in HIV care are often not straightforward, but rather complex and dynamic. People living with HIV may transition in and out of treatment and care throughout their lifetime. Therefore, a single undetectable viral load may not equate to true virologic suppression in an individual, but rather only a snapshot. This has the potential for an inaccurate picture of HIV burden and transmission risk in a population.

Within this study, researchers used the longitudinal measures of durable viral suppression, viraemia copy years and time without viral load suppression to assess disease burden and HIV transmission risk in the United States of America. The analysis involved people ages 13 years or older diagnosed with HIV before 2011 and in care in one of 17 jurisdictions that reported complete CD4 and viral load data to the Centers for Disease Control and Prevention’s National HIV Surveillance System. Everyone had at least one viral load test in 2011 and at least two between 2012-2013, and all were alive at the end of 2013.

Of the 251 649 persons included, two thirds had durable viral suppression with all viral load values being <200 copies/mL over the two-year period. Of note, during the same time period an additional 20% (total 83%) of the cohort had a suppressed viral load on their latest test. This would have potentially underestimated disease burden if analysed in isolation. The remaining one-third, without durable viral suppression, had high plasma burden and spent substantial time without virologic suppression, increasing the risk of HIV transmission.  As would be expected, the percentages of persons with durable viral suppression were lower among people with gaps in care. Disparities in disease burden and transmission risk potential were seen in several other subgroups.

The use of longitudinal measures broadens insight into disease burden and transmission risk in this population. Of further interest would have been people that had no evidence of being in care in 2011 but had an unsuppressed viral load between 2012-13, thus contributing to the population disease burden. These people were unfortunately not included in the analyses but may increase overall population transmission risk over the two years.

The findings underscore the recognised need for focused care and treatment efforts to address these disparities in virologic suppression and improve retention in care in the United States of America. The study also encourages the use of longitudinal markers in informing public health planning and resource allocation.

Northern America
United States of America
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Community ART support groups: a partial solution for improving retention in care?

A decade of antiretroviral therapy scale-up in Mozambique: evaluation of outcome trends and new models of service delivery among more than 300 000 patients enrolled during 2004-2013.

Auld AF, Shiraishi RW, Couto A, Mbofana F, Colborn K, Alfredo C, Ellerbrock TV, Xavier C, Jobarteh K. J Acquir Immune Defic Syndr. 2016 Oct 1;73(2):e11-22. doi: 10.1097/QAI.0000000000001137.

Background: During 2004-2013 in Mozambique, 455 600 HIV-positive adults (≥15 years old) initiated antiretroviral therapy (ART). We evaluated trends in patient characteristics and outcomes during 2004-2013, outcomes of universal treatment for pregnant women (Option B+) implemented since 2013, and effect on outcomes of distributing ART to stable patients through Community ART Support Groups (CASG) since 2010.

Methods: Data for 306 335 adults starting ART during 2004-2013 at 170 ART facilities were analyzed. Mortality and loss to follow-up (LTFU) were estimated using competing risks models. Outcome determinants were estimated using proportional hazards models, including CASG participation as a time-varying covariate.

Results: Compared with ART enrollees in 2004, enrollees in 2013 were more commonly female (55% vs. 73%), more commonly pregnant if female (<1% vs. 30%), and had a higher median baseline CD4 count (139 vs. 235/µL). During 2004-2013, observed 6-month mortality declined from 7% to 2% but LTFU increased from 24% to 30%. Pregnant women starting ART with CD4 count >350/µL and WHO stage I/II under Option B+ guidelines in 2013 had low 6-month mortality (0.1%) but high 6-month LTFU (38%). During 2010-2013, 6766 patients joined CASGs. In multivariable analysis, compared with nonparticipation in CASG, CASG participation was associated with 35% lower LTFU but similar mortality.

Conclusions: Initiation of ART at earlier disease stages in later calendar years might explain observed declines in mortality. Retention interventions are needed to address trends of increasing LTFU overall and the high LTFU among Option B+ pregnant women specifically. Further expansion of CASG could help reduce LTFU.

Abstract access  

Editor’s notes: The UNAIDS 90–90–90 treatment target for 2020 calls for 90% of all people with HIV to be diagnosed, 90% of people with HIV diagnosed to receive ART and 90% of people on ART to have a suppressed viral load. To maximise the impact of ART, people living with HIV should be diagnosed early, initiated on ART and retained in ART care.  Engagement along the complete treatment cascade will determine the long-term success of the global response to HIV. 

This manuscript describes the trends in patient characteristics and outcomes over the first decade of scale-up of ART in Mozambique (2004-2013). During this period close to half a million people living with HIV were initiated on ART; six-month mortality declined from 7% to 2% but six-month loss to follow-up (LTFU) increased from 24% to 30%. The authors found that later calendar year of ART was associated with higher risk of LTFU; an increase in “silent” transfers (undocumented transfer between health facilities) might have contributed to this. There was an increasing female-to-male ratio over calendar period during the study, most likely due to scale-up of HIV testing during antenatal care and (since 2013) implementation of Option B+ (initiation of lifelong ART for all pregnant women). The authors conclude that increased enrolment among men is necessary to reduce the disproportionally high HIV-associated morbidity and mortality among men.  

Interestingly, this is the first study to report on nationwide outcomes of community ART support groups (CASG), and to quantify the effect of CASG on LTFU. Consistent with the recent systematic review by Nachega and colleagues (included in this issue of HIV This Month), the authors found no difference in mortality between patients who received their ART through CASG and patients who received their ART from facilities. Also consistent with this systematic review, CASG participation was associated with 35% lower LTFU rates. The authors therefore suggest ART distribution through CASG as a potential partial solution. Possible reasons for lower LTFU rates among CASG participants include reduced patient transport cost, reduced patient time at the clinic, increased patient accountability, and improved social support. However, the authors acknowledged that people agreeing to join a CASG might be people who would in any event be retained in care. CASG participants were more commonly unemployed and uneducated than non-participants, which might indicate that CASG participation is more attractive for patients with fewer financial resources.  

Men were less likely to participate in CASGs, emphasizing again the need for male-specific programmes. The authors advocate for further research, and suggest offering male-only CASG as a possible way to improve male participation in CASG.

Africa
Mozambique
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No evidence of an increased risk of female-male HIV transmission with hormonal contraception in Zambia

Hormonal contraceptive use among HIV-positive women and HIV transmission risk to male partners, Zambia, 1994-2012.

Wall KM, Kilembe W, Vwalika B, Ravindhran P, Khu NH, Brill I, Chomba E, Johnson BA, Haddad LB, Tichacek A, Allen S. J Infect Dis. 2016 Oct 1;214(7):1063-71. doi: 10.1093/infdis/jiw322. Epub 2016 Jul 26.

Background: Evidence on the association between female-to-male human immunodeficiency virus (HIV) transmission risk and hormonal contraception is sparse and conflicting.

Methods: Heterosexual HIV-discordant couples from Lusaka, Zambia, were followed longitudinally at 3 month-intervals from 1994 to 2012. The impact of hormonal contraception on time to HIV transmission from HIV-positive women to their HIV-negative male partners (M-F+) was evaluated.

Results: Among 1601 M-F+ couples, 171 genetically linked HIV transmissions occurred in men over 3216 couple-years (5.3 transmissions/100 couple-years; 95% confidence interval [CI], 4.5-6.2). In multivariable Cox models, neither injectable (adjusted hazard ratio [aHR], 0.6; 95% CI, .4-1.2), oral contraceptive pill (aHR, 0.8; 95% CI, .3-2.1), nor implant (aHR, 0.8; 95% CI, .5-1.4) use was associated with HIV transmission, relative to nonhormonal methods, after controlling for the man's age at baseline and time-varying measures of pregnancy, self-reported unprotected sex with the study partner, sperm present on a vaginal swab wet mount, genital inflammation of either partner, genital ulceration of the man, and first follow-up interval. Sensitivity analyses, including marginal structural modeling and controlling for viral load and fertility intentions available in a subset of couples, led to similar conclusions.

Conclusions: Our findings suggest null associations between hormonal contraception and risk of female-to-male HIV transmission. We support efforts to increase the contraceptive method mix for all women, regardless of HIV serostatus, along with reinforced condom counseling for HIV-serodiscordant couples.

Abstract  Full-text [free] access 

Editor’s notes: Evidence suggests that certain injectable hormonal contraceptives (particularly depot medroxyprogesterone acetate [DMPA]) may increase HIV risk in women. However, few studies have assessed whether hormonal contraception increases the risk of female-male transmission. This paper presents results from an 18-year prospective follow-up study in Zambia. In the study, the investigators were able to analyse biologically linked results of serodiscordant couples and multiple methods of contraception. Their findings suggest no evidence of an increased risk of HIV transmission from women living with HIV to their male partners. In fact, couples with a linked transmission were less likely to use injectable contraceptives than women using non-hormonal methods (not statistically significant). This is encouraging; however, there are potential confounding factors in this study, such as high circumcision rates among men and low viral loads among women. The results also conflict with two earlier studies that found an increased risk of female-male transmission associated with hormonal contraception. More research is therefore necessary to provide evidence on this topic and enable recommendations on the use of hormonal contraception among serodiscordant couples.

Africa
Zambia
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Migrations, even over short distances, substantially increase the risk of HIV acquisition in rural South Africa

Space-time migration patterns and risk of HIV acquisition in rural South Africa: a population-based cohort study.

Dobra A, Barnighausen T, Vandormael A, Tanser F. AIDS. 2016 Oct 14. [Epub ahead of print]

Objective: To quantify the space-time dimensions of human mobility in relationship to the risk of HIV acquisition.

Methods: We used data from the population cohort located in a high HIV-prevalence, rural population in KwaZulu-Natal, South Africa (2000 - 2014). We geolocated 8006 migration events (representing 1 028 782 km travelled) for 17 743 individuals (≥15 years of age) who were HIV-negative at baseline and followed-up these individuals for HIV acquisition (70 395 person-years). Based on the complete geolocated residential history of every individual in this cohort, we constructed two detailed time-varying migration indices. We then used interval-censored Cox proportional hazards models to quantify the relationship between the migration indices and the risk of HIV acquisition.

Results: 17.4% of participants migrated at least once outside the rural study community during the period of observation (median migration distance = 107.1 km, IQR 18.9-387.5). The two migration indices were highly predictive of hazard of HIV acquisition (p < 0.01) in both men and women. Holding other factors equal, the risk of acquiring HIV infection increased by 50% for migration distances of 40 km (men) and 109 km (women). HIV acquisition risk also increased by 50% when participants spent 44% (men) and 90% (women) of their respective time outside the rural study community.

Conclusion: This in-depth analysis of a population cohort in a rural sub-Saharan African population has revealed a clear non-linear relationship between distance migrated and HIV acquisition. Our findings show that even relatively short distance migration events confer substantial additional risk of acquisition.

Abstract access  

Editor’s notes: Many studies in sub-Saharan African settings have illustrated that migrants have a greater risk of HIV infection and subsequent HIV-associated mortality than their non-migrant peers. The causal mechanisms underlying this enhanced risk and the temporal sequence of the migration and HIV acquisition events are less well understood. This study conducted in rural KwaZulu-Natal in South Africa is a longitudinal analysis linking data on migration episodes and the results of repeated HIV tests for individuals who were HIV negative at baseline. The two places of residence associated with the migration event were geo-coded, enabling the associations between spatiotemporal aspects of the migration and the risk of HIV acquisition to be explored. Two migration indices were calculated - one measuring the length of time spent outside the home residence and the other measuring the sum of the distances associated with the migrations. Both migration indices were significantly associated the risk of HIV acquisition. The association with distance was non-linear, with the risk of acquisition increasing by 50% at relatively short distances (approximately 55km), and the rates of increase of risk declined as the distance of migration increased further. The magnitude of this effect was similar for both sexes. By contrast the effect of time spent away from home on the risk of acquisition of HIV was significantly greater for men than women.

There are likely to be a number of mechanisms explaining the increased risks for migrants. These include an increase in the number of sexual partners, adoption of higher risk sexual behaviour and a detachment from the social support networks that exist in the home community. Further qualitative studies are necessary to explore these more fully. The authors also recommend that such studies are replicated in other settings to assess the generalisability of the findings. Having established these causal pathways, novel HIV prevention approaches focused towards these highly vulnerable migrant populations will need to be developed as part of efforts to achieve the UNAIDS 90:90:90 treatment target.

Africa
South Africa
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HIV incidence halved among injecting drugs users in network outreach programme - Ukraine

HIV incidence among people who inject drugs (PWIDs) in Ukraine: results from a clustered randomised trial.

Booth RE, Davis JM, Dvoryak S, Brewster JT, Lisovska O, Strathdee SA, Latkin CA. Lancet HIV. 2016 Oct;3(10):e482-9. doi: 10.1016/S2352-3018(16)30040-6. Epub 2016 Jul 29.

Background: HIV prevalence among people who inject drugs (PWID) in Ukraine is among the highest in the world. In this study, we aimed to assess whether a social network intervention was superior to HIV testing and counselling in affecting HIV incidence among PWID. Although this was not the primary aim of the study, it is associated with reducing drug and sex risk behaviours, which were primary aims.

Methods: In this clustered randomised trial, PWID who were 16 years of age or older, had used self-reported drug injection in the past 30 days, were willing to be interviewed for about 1 hour and tested for HIV, were not too impaired to comprehend and provide informed consent, and, for this paper, who tested HIV negative at baseline were recruited from the streets by project outreach workers in three cities in southern and eastern Ukraine: Odessa, Donetsk, and Nikolayev. Index or peer leaders, along with two of their network members, were randomly assigned (1:1) by the study statistician to the testing and counselling block (control group) or the testing and counselling plus a social network intervention block (intervention group). No stratification or minimisation was done. Participants in the network intervention received five sessions to train their network members in risk reduction. Those participants assigned to the control group received no further intervention after counselling. The main outcome of this study was HIV seroconversion in the intent-to-treat population as estimated with Cox regression and incorporating a gamma frailty term to account for clustering. This trial is registered with ClinicalTrial.gov, number NCT01159704.

Findings: Between July 12, 2010, and Nov 23, 2012, 2304 PWIDs were recruited, 1200 of whom were HIV negative and are included in the present study. 589 index or peer leaders were randomly assigned to the control group and 611 were assigned to the intervention group. Of the 1200 HIV-negative participants, 1085 (90%) were retained at 12 months. In 553.0 person-years in the intervention group, 102 participants had seroconversion (incidence density 18.45 per 100 person-years; 95% CI 14.87-22.03); in 497.1 person-years in the control group 158 participants seroconverted (31.78 per 100 person-years; 26.83-36.74). This corresponded to a reduced hazard in the intervention group (hazard ratio 0.53, 95% CI 0.38-0.76, p=0.0003). No study-related adverse events were reported.

Interpretation: These data provide strong support for integrating peer education into comprehensive HIV prevention programmes for PWID and suggest the value in developing and testing peer-led interventions to improve access and adherence to pre-exposure prophylaxis and antiretroviral therapy.

Abstract  Full-text [free] access 

Editor’s notes: People who inject drugs are at high risk of HIV infection, and, in many settings, are unlikely to have appropriate access to HIV prevention programmes. This study is a secondary, subgroup analysis of a randomised control of a social network programme for people who inject drugs in Ukraine (the primary outcome was HIV risk taking behaviour). The investigators recruited 256 index users, who subsequently recruited fellow members of their injection network to the study. Half (n=128) of the index participants were randomized to a two-week training programme in risk reduction education. These “peer leaders” were trained with the intention that they would disseminate these skills within their injection networks. The HIV incidence was alarmingly high. After 12 months, for the sub-group of participants who were initially HIV-negative, the incidence of seroconversion was 31.9/100 person-years in the control networks and 18.4/100 person-years in the programme networks, representing a 47% reduction in incidence associated with the programme. This study is notable for its randomized design, low attrition, close collaboration with local non-governmental organizations, a study protocol adaptation process which engaged drugs users and dealers, and a biological outcome measure. Further research can consider the economic costs for each averted HIV infection, whether the programme effects varied by other factors, and assessment of the extent to which the risk reduction skills were shared beyond study participants. The very high incidence, even among those receiving the intervention, emphasize the need for much greater investment in harm reduction approaches.

Europe
Ukraine
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Worms and HIV – time to end the debate?

Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study.

Kroidl I, Saathoff E, Maganga L, Makunde WH, Hoerauf A, Geldmacher C, Clowes P, Maboko L, Hoelscher M. Lancet. 2016 Oct 15;388(10054):1912-1920. doi: 10.1016/S0140-6736(16)31252-1. Epub 2016 Aug 3.

Background: The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania.

Methods: In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis.

Findings: Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly      18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1.91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0.80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2.17 (95% CI 1.08-4.37, p=0.0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors.

Interpretation: To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented.

Abstract access    

Editor’s notes: The interest in the link between helminth infections and HIV is based on our understanding of how helminth infections affect the human immune system. One core hypothesis has been that the shift to a predominantly T-helper type 2 (Th2) immune response associated with helminth infection might increase the risk of HIV acquisition. Until now, there has been no compelling evidence to support this. Observational studies looking at co-prevalence of HIV and filarial infection have not consistently illustrated an association between filarial infection and prevalent HIV infection. This relatively large population-based cohort study allowed a different approach, exploring the association between helminth infection and incident HIV infection over an average of three years follow-up. The presence of circulating filarial antigens doubled the risk of HIV acquisition.

So do the findings of this study end the debate? Perhaps not. The analysis did not account for the presence or absence of other helminth infections around the time of HIV acquisition. Also, although the analysis controlled for some socio-economic and behavioural factors known to be associated with HIV acquisition, this was incomplete so there is the possibility of residual confounding.

The findings from this study have led to renewed calls for clinical trials to evaluate the effect of antihelminthic treatment on HIV acquisition, but it may be too late. Elimination of neglected tropical diseases (including filariasis) is a global health priority in its own right, as is scale-up of combination HIV prevention strategies, including universal test and treat and pre-exposure prophylaxis. Clinical trials might therefore require unfeasibly large sample sizes to demonstrate an independent effect of antihelminthic treatment.

Africa
United Republic of Tanzania
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Standard methods underestimate the effect of HIV on fertility

The effects of HIV on fertility by infection duration: evidence from African population cohorts before ART availability: fertility by duration of HIV infection.

Marston M, Nakiyingi-Miiro J, Kusemererwa S, Urassa M, Michael D, Nyamukapa C, Gregson S, Zaba B, Eaton JW. AIDS. 2016 Oct 20. [Epub ahead of print]

Objectives: To estimate the relationship between HIV natural history and fertility by duration of infection in East and Southern Africa before the availability of antiretroviral therapy, and assess potential biases in estimates of age-specific sub-fertility when using retrospective birth histories in cross-sectional studies.

Design: Pooled analysis of prospective population-based HIV cohort studies in Masaka (Uganda) Kisesa (Tanzania), and Manicaland (Zimbabwe).

Methods: Women aged 15-49 who had ever tested for HIV were included. Analyses were censored at antiretroviral treatment roll out. Fertility rate ratios were calculated to see the relationship of duration of HIV infection on fertility, adjusting for background characteristics. Survivorship and misclassification biases on age-specific subfertility estimates from cross-sectional surveys were estimated by reclassifying person time from the cohort data to simulate cross-sectional surveys and comparing fertility rate ratios to true cohort results.

Results: HIV negative and positive women contributed 15 440 births and 86 320 person years; and 1236 births and 11 240 thousand person years respectively to the final dataset. Adjusting for age, study site and calendar year, each additional year since HIV sero conversion was associated with a 0.02 (95%CI 0.01-0.03) relative decrease in fertility for HIV-positive women. Survivorship and misclassification biases in simulated retrospective birth histories resulted in modest underestimates of sub-fertility by 2-5% for age groups 20-39y.

Conclusion: Longer duration of infection is associated with greater relative fertility reduction for HIV-positive women. This should be considered when creating estimates for HIV prevalence among pregnant women and PMTCT need over the course of the HIV epidemic and ART scale-up.

Abstract access 

Editor’s notes: HIV prevalence among antenatal clinic attenders is used to help estimate population HIV prevalence. It is known that figures must be adjusted upwards to reflect the fact HIV reduces fertility, especially in older women. However, older women are also likely to have been living with HIV for longer. The authors investigated whether length of infection changes the effect of HIV on fertility. Using three prospective longitudinal cohorts, they found that time since seroconversion was associated with reduced fertility, even after adjusting for age and age at seroconversion. This result is important because as the epidemic matures and the majority of women living with HIV are not recently infected, the effect of HIV on suppressing fertility will increase. This will cause measurements of HIV prevalence in pregnancy to underestimate the true population prevalence even if they adjust for age. Conversely, women who have been living with HIV for longer are more likely to be taking ART, which increases fertility relative to women who have been diagnosed more recently. Therefore, within an age-group, pregnancy data is likely to overestimate the proportion of HIV positive women on ART. The usual way to measure the age-specific effects of HIV on fertility is to compare the three-year reported fertility of women living with HIV, and women without HIV in a cross-sectional survey. The authors used longitudinal data to simulate a survey and showed that surveys slightly underestimate the size of the fertility effect, for two reasons. Firstly, if women acquire HIV during the three years any pregnancies before infection are misattributed to HIV. Secondly, there is excess mortality of HIV positive women with low fertility who therefore do not appear in the survey.

The reasons for the age-dependent effect of HIV on fertility are both biological and social (older women living with HIV are more likely to be widowed or divorced) and the relationship is not fixed over time. It shifts according to demographic factors, the stage of the epidemic and, availability of treatment. Assumptions must be continually tested as the epidemic evolves. 

Epidemiology
Africa
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High mortality persists among people presenting with advanced HIV disease

Mortality in the first 3 months on antiretroviral therapy among HIV-positive adults in low- and middle-income countries: a meta-analysis.

Brennan AT, Long L, Useem J, Garrison L, Fox MP. J Acquir Immune Defic Syndr. 2016 Sep 1;73(1):1-10. doi: 10.1097/QAI.0000000000001112.

Previous meta-analyses reported mortality estimates of 12-month post-antiretroviral therapy (ART) initiation; however, 40%-60% of deaths occur in the first 3 months on ART, a more sensitive measure of averted deaths through early ART initiation. To determine whether early mortality is dropping as treatment thresholds have increased, we reviewed studies of 3 months on ART initiation in low- to middle-income countries. Studies of 3-month mortality from January 2003 to April 2016 were searched in 5 databases. Articles were included that reported 3-month mortality from a low- to middle-income country; nontrial setting and participants were ≥15. We assessed overall mortality and stratified by year using random effects models. Among 58 included studies, although not significant, pooled estimates show a decline in mortality when comparing studies whose enrollment of patients ended before 2010 (7.0%; 95% CI: 6.0 to 8.0) with the studies during or after 2010 (4.0%; 95% CI: 3.0 to 5.0). To continue to reduce early HIV-related mortality at the population level, intensified efforts to increase demand for ART through active testing and facilitated referral should be a priority. Continued financial investments by multinational partners and the implementation of creative interventions to mitigate multidimensional complex barriers of accessing care and treatment for HIV are needed.

Abstract access  

Editor’s notes: Early mortality among people initiating antiretroviral therapy (ART) remains high, presumed to be because many people living with HIV present when already very sick with advanced HIV disease. This systematic review included 43 studies from Africa and 13 from Asia. Its main aim was to see whether the evolution of guidelines recommending ART initiation at progressively higher CD4 counts over this period had reduced early mortality (defined as death within three months of ART start) and, by implication, the proportion of people starting ART who had advanced disease. To investigate this, the authors compared studies where enrolment ended before 2010 with studies that had started later.

Overall early mortality was six percent.  Because of the large numbers lost to follow up this will be an underestimate. The authors attempted to compensate for this, and calculated an adjusted overall figure of more than 10%. There was a fall in early mortality from seven percent to four percent (unadjusted) between the early and late periods but although the trend was consistent the difference was not significant.

In only four of the 58 studies was the median CD4 count at ART initiation above 200x106/l. It seems likely that even when policies to initiate ART at high CD4 counts are adopted, additional efforts will be necessary to promote initiation of ART and retention in care for people who feel well.  This is in order to reduce the number of people starting ART with advanced disease and consequently at very high risk of early death.   

Africa, Asia, Latin America
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