SummaryBackground

Secondary distribution of HIV self-testing (HIVST) kits by patients attending clinic services to their partners could improve the rate of HIV diagnosis. We aimed to investigate whether secondary administration of HIVST kits, with or without an additional financial incentive, via women receiving antenatal care (ANC) or via people newly diagnosed with HIV (ie, index patients) could improve the proportion of male partners tested or the number of people newly diagnosed with HIV.

MethodsWe did a three-arm, open-label, pragmatic, cluster-randomised trial of 27 health centres (clusters), eligible if they were a government primary health centre providing ANC, HIV testing, and ART services, across four districts of Malawi. We recruited women (aged ≥18 years) attending their first ANC visit and whose male partner was available, not already taking ART, and not already tested for HIV during this pregnancy (ANC cohort), and people (aged ≥18 years) with newly diagnosed HIV during routine clinic HIV testing who had at least one sexual contact not already known to be HIV-positive (index cohort). Centres were randomly assigned (1:1:1), using a public selection of computer-generated random allocations, to enhanced standard of care (including an invitation for partners to attend HIV testing services), HIVST only, or HIVST plus a US$10 financial incentive for retesting. The primary outcome for the ANC cohort was the proportion of male partners reportedly tested, as ascertained by interview with women in this cohort at day 28. The primary outcome for the index cohort was the geometric mean number of new HIV-positive people identified per facility within 28 days of enrolment, as measured by observed HIV test results. Cluster-level summaries compared intervention with standard of care by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03705611.Findings

Between Sept 8, 2018, and May 2, 2019, nine clusters were assigned to each trial arm, resulting in 4544 eligible women in the ANC cohort (1447 [31·8%] in the standard care group, 1465 [32·2%] in the HIVST only group, and 1632 [35·9%] in HIVST plus financial incentive group) and 708 eligible patients in the index cohort (234 [33·1%] in the standard care group, 169 [23·9%] in the HIVST only group, and 305 [42·9%] in the HIVST plus financial incentive group). 4461 (98·2%) of 4544 eligible women in the ANC cohort and 645 (91·1%) of 708 eligible patients in the index cohort were recruited, of whom 3378 (75·7%) in the ANC cohort and 439 (68·1%) in the index cohort were interviewed after 28 days. In the ANC cohort, the mean proportion of reported partner testing per cluster was 35·0% (SD 10·0) in the standard care group, 73·0% in HIVST only group (13·1, adjusted risk ratio [RR] 1·71, 95% CI 1·48–1·98; p<0·0001), and 65·2% in the HIVST plus financial incentive group (11·6, adjusted RR 1·62, 1·45–1·81; p<0·0001). In the index cohort, the geometric mean number of new HIV-positive sexual partners per cluster was 1·35 (SD 1·62) for the standard care group, 1·91 (1·78) for the HIVST only group (incidence rate ratio adjusted for number eligible as an offset in the negative binomial model 1·65, 95% CI 0·49–5·55; p=0·3370), and 3·20 (3·81) for the HIVST plus financial incentive group (3·11, 0·99–9·77; p=0·0440). Four self-resolving, temporary marital separations occurred due to disagreement in couples regarding HIV self-test kits.

Interpretation

Although administration of HIVST kits in the ANC cohort, even when offered alongside a financial incentive, did not identify significantly more male patients with HIV than did standard care, out-of-clinic options for HIV testing appear more acceptable to many male partners of women with HIV, increasing test uptake. Viewed in the current context, this approach might allow continuation of services despite COVID-19-related lockdowns.

Funding

Unitaid, through the Self-Testing Africa Initiative.

IntroductionTesting plays a key role in control of infectious diseases, including HIV, and it is crucial for diagnosis, treatment, and prevention. Men aged 30 years and older, adolescents, the most economically disadvantaged people, and key populations (eg, men who have sex with men, sex workers, etc) have a high risk of undiagnosed HIV, and they report facing substantial barriers to standard facility-based HIV testing services.1WHO
Consolidated guidelines on HIV testing services for a changing epidemic: policy brief. HIV self-testing (HIVST) provides a convenient, intrinsically confidential, and often preferred testing approach that can bypass facility access barriers, such as high indirect and opportunity costs, worries about confidentiality or reliability of routine services, and anticipated stigma.2WHO
Guidelines on HIV self-testing and partner notification. Supplement to consolidated guidelines on HIV testing services. HIVST was fully endorsed by WHO as a recommended approach to providing HIV testing services in November, 2019, and it is promoted as an important tool for reaching HIV elimination targets in all global regions by international disease control initiatives (eg, the US Agency for International Development–President's Emergency Plan for AIDS Relief).1WHO
Consolidated guidelines on HIV testing services for a changing epidemic: policy brief., 3UNAIDS
Global AIDS Monitoring. HIVST also provides an evidence-based option to maintain HIV testing services, despite disruption to routine service delivery from the COVID-19 pandemic.1WHO
Consolidated guidelines on HIV testing services for a changing epidemic: policy brief.Among the most promising HIVST delivery strategies is secondary distribution, whereby patients attending clinic services take kits home for their sexual partners.4Choko AT Corbett EL Stallard N et al.HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: an adaptive multi-arm, multi-stage cluster randomised trial., 5Masters SH Agot K Obonyo B Napierala Mavedzenge S Maman S Thirumurthy H Promoting partner testing and couples testing through secondary distribution of HIV self-tests: a randomized clinical trial., 6Thirumurthy H Masters SH Mavedzenge SN Maman S Omanga E Agot K Promoting male partner HIV testing and safer sexual decision making through secondary distribution of self-tests by HIV-negative female sex workers and women receiving antenatal and post-partum care in Kenya: a cohort study. Secondary distribution from antenatal care (ANC) clinics is safe,7Kumwenda MK Johnson CC Choko AT et al.Exploring social harms during distribution of HIV self-testing kits using mixed-methods approaches in Malawi. acceptable to both partners, and the only approach tried, to date, that results in high uptake of HIV testing by male partners of pregnant women,4Choko AT Corbett EL Stallard N et al.HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: an adaptive multi-arm, multi-stage cluster randomised trial., 5Masters SH Agot K Obonyo B Napierala Mavedzenge S Maman S Thirumurthy H Promoting partner testing and couples testing through secondary distribution of HIV self-tests: a randomized clinical trial., 6Thirumurthy H Masters SH Mavedzenge SN Maman S Omanga E Agot K Promoting male partner HIV testing and safer sexual decision making through secondary distribution of self-tests by HIV-negative female sex workers and women receiving antenatal and post-partum care in Kenya: a cohort study. which is a key component of strategies for eliminating paediatric HIV.8Drake AL Wagner A Richardson B John-Stewart G Incident HIV during pregnancy and postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-analysis. Although less well defined, secondary distribution of HIVST kits also holds promise as an additional way to test the sexual partners of people with newly diagnosed HIV (so-called index testing).2WHO
Guidelines on HIV self-testing and partner notification. Supplement to consolidated guidelines on HIV testing services. Index testing provides a high yield of newly diagnosed HIV-positive people globally;9Lasry A Medley A Behel S et al.scaling up testing for human immunodeficiency virus infection among contacts of index patients–20 countries, 2016–2018. however, this approach was only endorsed in 2016–19 by HIV programmes because of concerns around confidentiality, stigma, and the safety of index patients and their partners, as well as feasibility due to existing laws and policies, and limited resources to support providers with ongoing training, monitoring, and supervision.Malawi is a country in southeast Africa that has a high HIV prevalence, with an estimated adult prevalence of 9·2%. Undiagnosed HIV and the incidence of new HIV infection in adults and neonates have been substantially reduced by a highly efficient and pragmatic HIV testing and antiretroviral therapy (ART) programme, with an estimated 90·0% of people living with HIV diagnosed and 87·0% of those receiving ART in 2018. Nevertheless, providing HIV testing to male partners of pregnant women during pregnancy has remained an important gap, contributing to new HIV infections in pregnant and breastfeeding women that now account for a high proportion of all perinatal HIV infections in Malawi.11Choko AT Kumwenda MK Johnson CC et al.Acceptability of woman-delivered HIV self-testing to the male partner, and additional interventions: a qualitative study of antenatal care participants in Malawi. Index testing has been routinely implemented by use of patient referral or an invitation by letter (eg, family referral slip) for all partners and family members of people with newly diagnosed HIV to attend for HIV testing, without further active follow-up.12Tembo TA Kim MH Simon KR et al.Enhancing an HIV index case testing passive referral model through a behavioural skills-building training for healthcare providers: a pre-/post-assessment in Mangochi District, Malawi.Financial incentives address economic barriers associated with HIV testing and care, including direct and opportunity costs, especially for men.13Sakala D Kumwenda MK Conserve DF Ebenso B Choko AT Socio-cultural and economic barriers, and facilitators influencing men's involvement in antenatal care including HIV testing: a qualitative study from urban Blantyre, Malawi. A growing body of literature suggests that the use of financial incentives increases HIV testing and clinic attendance for HIV services, including ART initiation, especially in hard-to-reach groups such as men.4Choko AT Corbett EL Stallard N et al.HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: an adaptive multi-arm, multi-stage cluster randomised trial., 14Choko AT Candfield S Maheswaran H Lepine A Corbett EL Fielding K The effect of demand-side financial incentives for increasing linkage into HIV treatment and voluntary medical male circumcision: a systematic review and meta-analysis of randomised controlled trials in low- and middle-income countries. However, in resource-limited settings with heightened amounts of corruption, few delivery platforms, and personal risk to staff, use of financial incentives is largely unsupported by policy makers.

In this study, set in Malawi, we aimed to investigate whether secondary administration of HIVST kits, in the presence or absence of an additional financial incentive, via women receiving ANC could improve the proportion of male partners being tested. We also aimed to investigate whether secondary administration of these test kits, with or without a financial incentive, via people who had been newly diagnosed with HIV (ie, index patients) could improve the number of people newly diagnosed with HIV.

Methods Study design and participantsWe did a three-arm, open-label, pragmatic, cluster-randomised trial of 27 government health centres (clusters) across four districts (Blantyre, Zomba, Thyolo, and Mulanje) of Malawi. Centres were eligible to be a cluster if they were a government primary health clinic or centre providing ANC, HIV testing, and ART services. The minimum distance between any two clusters was 5 km, which substantially reduced or eliminated any potential contamination. Each cluster enrolled women attending ANC (ANC cohort) and people with newly diagnosed HIV during routine clinic HIV testing (index cohort) into one of three trial arms (standard of care, HIVST only, and HIVST plus financial incentive). Each health centre recruited participants for both cohorts. HIVST kits were provided by routine health staff after verbal consent was obtained, given that all components were already national policy. Leaflets for recipients explained that data would be used for a research study. Written informed consent was obtained from all participants within clusters assigned to the HIVST plus financial incentive group, as well as their sexual partners, who all took part in a diagnostic accuracy substudy. Ethics approval was obtained from the Malawi College of Medicine Research Ethics Committee (P.02/18/2352) and London School of Hygiene & Tropical Medicine Ethics Committee (14916). Although there is potential for harm resulting from false positive or false negative HIVST results and coercion, the evidence indicates negligible social harms from introducing HIVST.7Kumwenda MK Johnson CC Choko AT et al.Exploring social harms during distribution of HIV self-testing kits using mixed-methods approaches in Malawi., 15Ethical implications of HIV self-testing.

Eligible women attending ANC were enrolled into the ANC clinic cohort unless newly diagnosed with HIV, in which case they would be enrolled into the index cohort. Depending on the trial arm they were assigned to, women were provided with materials and brief training for their male partner, assuming only one probable father. We included women who were attending their first ANC visit; aged at least 18 years; intending to remain in the clinic catchment area; not already enrolled; and whose male partner (ie, the child's probable father) was present and reachable, not already receiving ART, or not already tested during this pregnancy. We excluded women if their male partner was aged younger than 18 years, already receiving ART, and not presently available and resident in the catchment area.

People newly diagnosed with HIV during routine clinic HIV testing, including pregnant women, were enrolled into the index cohort. We included individuals who were aged at least 18 years, intending to remain in the clinic catchment area, not already enrolled, and had at least one sexual contact (ie, contactable sexual partner) not already known to be HIV-positive. We excluded index patients if all of their sexual contacts were aged younger than 18 years or were already receiving ART, or if none were presently available and resident in the catchment area. Depending on the trial arm they were assigned to, index patients were provided with materials and brief training, and asked to deliver materials to all sexual contacts over the past 12 months. The number of sexual contacts per index patient varied on the basis of the number of contactable sexual partners.

 Randomisation and masking

Restricted randomisation (blocking) was used to randomise the 27 clusters to three arms in a ratio of 1:1:1, with district and HIV prevalence in ANC as the variables for restriction. The first group was enhanced standard of care (standard care group), which only offered letters inviting male partners or sexual contacts to attend HIV testing services at the clinic. The second group was HIVST only (HIVST only group), which offered invitation letters plus oral HIVST kits to the pregnant women to deliver to their male partners or to the index patients to deliver to their sexual contacts. The third group was HIVST with an additional financial incentive (HIVST plus financial incentive group), which offered male partners or sexual contacts US$10 to retest at the clinic following self-testing, irrespective of HIV status. A statistician (MN) generated a list of 100 000 randomisation options meeting the restriction criteria and chose one of these options at random using a computer programme. At a public ceremony held on June 29, 2018, representatives of the 27 primary health centres and hospitals were split into three groups according to the letters of their randomisation allocation. Each group chose a team name and a team captain. The team captains drew a golf ball at random, which was prelabelled with the trial arm to be implemented at the nine clinics within their group.

Due to the nature of the interventions, clinic personnel and participants could not be masked to allocation; however, data were managed by an appointed data manager without reference to the trial arm to maintain investigator masking until final analysis.

 Procedures

In the standard care group, letters (ie, standard family referral slips) were used to invite male partners of women in the ANC cohort or sexual partners of patients in the index cohort to attend HIV testing services within 28 days of enrolment. The HIVST only group used the approach intended for routine adoption in Malawi, with only HIV-positive partners advised to return for confirmation and HIV care. The HIVST plus financial incentive group allowed the diagnostic accuracy of HIVST kits distributed in this way to be investigated. The participant's own interpretation of HIVST results and results obtained from retesting by the HIV provider were compared. This group was also offered voluntary male medical circumcision (VMMC) for uncircumcised men who were HIV-negative.

In the HIVST only group, women in the ANC cohort or patients in the index cohort were provided with one OraQuick HIV Self-Test (OraSure Technologies, Bethlehem, PA, USA) kit per sexual partner for secondary distribution, with a brief demonstration (approximately 5 min) on how to correctly open the kit, identify the instructions for use, run the test, and read the results. Partners were encouraged to attend clinic services to confirm all positive results or results that were serodiscordant (ie, one positive and one negative) with their regular partner.

In the HIVST plus financial incentive group, women in the ANC cohort or patients in the index cohort were, in addition to the test kit and demonstration, provided with a leaflet offering their male partner or sexual contacts $10 to retest at the clinic. Demand-side financial incentives (ie, incentives offered to users of health services) have become of interest in HIV, especially for increasing the uptake of testing and clinic attendance in priority populations.14Choko AT Candfield S Maheswaran H Lepine A Corbett EL Fielding K The effect of demand-side financial incentives for increasing linkage into HIV treatment and voluntary medical male circumcision: a systematic review and meta-analysis of randomised controlled trials in low- and middle-income countries.

Government staff managed secondary HIVST kit distribution and HIV care, including confirmatory testing and starting patients on ART. Follow-up interviews with women in the ANC cohort were completed by an interviewer, independent from the original kit distributor, at the next ANC visit (within 28 days) to ascertain male partner testing. There was no compensation for completing this interview.

Follow-up testing was done by accredited providers using two fingerprick rapid diagnostic tests in parallel (Determine [Abbott; Chicago, IL, USA] and Uni-Gold [Trinity Biotech; Bray, Ireland]) for all male partners or sexual contacts who collected their $10 incentive and reported having self-tested in the HIVST plus financial incentive group. HIVST results were self-reported, with inspection of used HIVST kits if brought by the client. Participants had to show a used HIVST kit; if the used HIVST was not available, the participant was asked to do a second HIVST before follow-up testing.

 Outcomes

The primary outcome for the ANC cohort was the proportion of male partners reportedly tested for HIV, as ascertained by interview with the woman attending ANC 28 days after enrolment. The primary outcome for the index cohort was the geometric mean number of HIV-positive people diagnosed per cluster, within 28 days of enrolling the index patient. To satisfy the primary outcome, within 28 days of enrolling the index patient, a sexual contact of a participant in the standard care group had to present the originally allocated letter to the clinic and test positive, and a sexual contact of a participant in the HIVST only group and HIVST plus financial incentive group had to bring a positive self-test result to be immediately confirmed.

Secondary outcomes for the ANC cohort were the proportion of male partners attending any HIV clinic services, or who started ART, underwent VMMC, or attended a discordant couples' clinic within 28 days of enrolling participants, using all eligible women as the denominator. A post-hoc analysis for this cohort was the proportion of male partners booked for VMMC, also using all eligible women as the denominator.

Secondary outcomes for the index cohort were the proportion of sexual contacts reportedly tested for HIV, as ascertained by interview with the index patient at day 28; the number of sexual contacts who attended the clinic for any HIV services; and the number of sexual contacts who started ART, underwent VMMC, or attended a discordant couples' clinic, within 28 days of the index patient's diagnosis. A secondary outcome for both cohorts was the percentage of adverse events (eg, partnership breakdown, intimate partner violence, etc) related to HIVST reported by participants, measured at day 28.

Outcomes were evaluated at day 28 by use of participant interviews and clinic registers, including phone calls for clients with missed interviews.

We also did a prespecified exploratory analysis of secondary accuracy of HIVST—the correctness (ie, sensitivity and specificity) with which the ultimate user (not necessarily the original recipient of the test kit) does the test—in the HIVST plus financial incentive group.

 Statistical analysisThe sample size calculation was based on the primary outcome of the ANC cohort, with nine clusters per arm and 350 pregnant women per cluster, providing 90% power to detect a 12% increase in partner HIV testing over an assumed 20% in the standard care group, using a coefficient of variation (k) of 0·25.4Choko AT Corbett EL Stallard N et al.HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: an adaptive multi-arm, multi-stage cluster randomised trial.ANC cohort analyses followed intention-to-treat principles, so all eligible women (not just those who participated) were included in the denominator.16Intention-to-treat concept: a review. A per-protocol post-hoc analysis16Intention-to-treat concept: a review. was also done for the ANC cohort, excluding women not interviewed at follow-up. The main hypothesis testing in the ANC cohort used cluster-level summaries and a t test due to the small number of clusters per arm, with methods appropriate for clustered trial designs.17Cluster randomised trials. In summary, the proportion achieving the primary outcome was computed for each cluster. The mean of proportions in each intervention arm was then compared with the mean of proportions in the standard care group with a t test. Risk ratios (RRs), risk differences, and 95% CIs were computed for male partner testing. A sensitivity analysis using random-effects logistic regression was done. For the primary outcome of the index cohort, analysis followed intention-to-treat principles. The geometric mean count of HIV-positive contacts was calculated, with a negative binomial model used for incidence rate ratios (IRR) comparing each intervention group with the standard care group, to account for overdispersion.

Analyses for the secondary outcomes followed intention-to-treat principles, with all male partners or sexual contacts achieving the outcome in the numerator and all eligible women in the ANC cohort or eligible patients in the index cohort in the denominator.

As a sensitivity analysis, an individual-level, random-effects logistic model was fitted for the ANC cohort to explore any potential differences from the main analysis.

To estimate secondary accuracy, the sensitivity and specificity and associated 95% CIs of participants' own interpretation of self-test results were computed by use of HIV provider-administered parallel rapid testing, with Uni-Gold (Abbott) and Determine (Biotech) as the reference.

Statistical analysis was done with R (version 5.1) and Stata (14.0).

 Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

ResultsWe completed this study between Sept 8, 2018, and May 2, 2019. In the ANC cohort, a total of 9939 women were assessed for eligibility, of whom 4544 (45·7%) were eligible (figure). 5395 (54·3%) women were excluded largely because they were accompanied by the male partner to the ANC visit. Nine clusters were randomly assigned to each group, resulting in 1447 (31·8%) of 4544 women in the standard care group, 1465 (32·2%) in the HIVST only group, and 1632 (35·9%) in the HIVST plus financial incentive group. 83 (1·8%) of 4544 eligible women did not consent to participate and were not recruited, but were still included in the analysis population: 51 (3·5%) of 1447 women in the standard of care group, 15 (1·0%) of 1465 in the HIVST only group, and 17 (1·0%) of 1632 in the HIVST plus financial incentive group. Of the 4461 women recruited, 315 (22·6%) of 1396 individuals in the standard care group, 285 (17·6%) of 1615 individuals in the HIVST only group, and 483 (33·3%) of 1450 individuals in the HIVST plus financial incentive group were lost to follow-up at 28 days. No cluster was lost to follow-up; hence, all clusters were included in the analysis and all eligible women were included in the analysis of the primary outcome.

FigureTrial profile

Show full caption

ANC=antenatal care. ART=antiretroviral therapy. HIVST=HIV self-testing.

In the index cohort, a total of 1480 index patients were assessed for eligibility, of whom 708 (47·8%) were eligible. We excluded 772 (52·2%) patients mostly due to their sexual contact already receiving ART. Nine clusters were randomly assigned to each group, resulting in 234 (33·1%) patients in the standard care group, 169 (23·9%) in the HIVST only group, and 305 (42·9%) in the HIVST plus financial incentive group. 63 (8·9%) of 708 eligible patients did not consent to participate and were not recruited, but were still included in the analysis population: 30 (12·8%) of 234 patients in the standard of care group, 16 (9·5%) of 169 in the HIVST only group, and 17 (5·6%) of 305 in the HIVST plus financial incentive group. Among the 645 index patients recruited, 48 (23·5%) of 204 individuals in the standard care group, 36 (23·5%) of 153 individuals in the HIVST only group, and 122 (42·4%) of 288 individuals in the HIVST plus financial incentive group were lost to follow-up at 28 days. No clusters were lost to follow-up and were all included in the analysis, with all eligible index patients included in the analysis of the primary outcome.

Baseline characteristics of women in the ANC cohort were reasonably balanced (table 1), except for illiteracy (247 [17·1%] of 1447 in the standard care group vs 95 [6·5%] of 1465 in the HIVST only and 104 [6·4%] of 1632 in the HIVST plus financial incentive group) and reported previous partner HIV testing more or less than 12 months ago (516 [35·7%] of 1447 in the standard care group vs 651 [44·4%] of 1465 in the HIVST only group and 899 [55·1%] of 1632 in the HIVST plus financial incentive group).

Table 1Characteristics of women in the ANC cohort and their male partners, as reported by these women at enrolment

Data are median (IQR) or n (%). HIVST=HIV self-testing. ANC=antenatal care.

For the index cohort, there was reasonable balance in baseline characteristics (table 2), although there were more men in the HIVST plus financial incentive group than in the HIVST only and standard care groups (99 [32·5%] of 305 vs 58 [24·8%] of 234 in the standard care group and 36 [21·3%] of 169 in the HIVST only group), and higher illiteracy in the standard care group (59 [25·2%] of 234) than in the HIVST only (22 [13·0%] of 169) and HIVST plus financial incentive (27 [8·8%] of 305) groups.

Table 2Characteristics of patients in the index cohort and their sexual contacts, as reported by index patients at enrolment

Data are median (IQR) or n (%). HIVST=HIV self-testing.

For the primary outcome in the ANC cohort, mean uptake per cluster of male partner HIV testing by 28 days, as reported by women in this cohort, was 73·0% (SD 13·1) in the HIVST only group and 65·2% (11·6) in the HIVST plus financial incentive group, compared with 35·0% (10·0) in the standard care group (table 3). In comparison with the standard care group, the adjusted RR was 1·71 (95% CI 1·48–1·98, ptable 3; appendix p 1). The coefficient of variation (k) for the male partner testing outcome was 0·15.

Table 3Reported testing of male partners of women in the ANC cohort and newly diagnosed HIV-positive people among sexual contacts of patients in the index cohort

Each trial arm had nine clusters. HIVST=HIV self-testing. ANC=antenatal care. RR=risk ratio.

For the primary outcome in the index cohort, the geometric mean number of new positive sexual partners per cluster was 1·35 (SD 1·62) for the standard care group, 1·91 (1·78) for the HIVST only group, and 3·20 (3·81) for the HIVST plus financial incentive group (table 3; appendix p 2). The HIVST plus financial incentive group had a higher incidence of newly diagnosed HIV-positive sexual contacts than did the standard care group (IRR 3·24, 95% CI 1·16–9·07; p=0·0250); however, there was no difference in rates between the HIVST only group and the standard care group (IRR 1·38, 0·45–4·16; p=0·5660). In an analysis adjusted for number of eligible index patients per cluster (which was more highly variable or overdispersed than anticipated in our statistical analysis plan), the evidence for difference with the HIVST plus financial incentive intervention was weaker, with an adjusted IRR of 3·11 (0·99–9·77; p=0·0440). The coefficient of variation (k) for the male partner testing outcome was 0·75.Secondary outcomes in the ANC cohort should be interpreted in light of the different instructions given per arm—ie, all partners were asked to attend clinic HIV services in the standard care and HIVST plus financial incentive groups, yet only men testing positive with HIVST and serodiscordant couples were asked to attend HIV services in the HIVST only group. Thus, the main comparison for the proportion of male partners attending any HIV clinic services was the standard care group versus the HIVST plus financial incentive group (table 4). Providing HIVST plus $10 for clinic attendance substantially increased male partner attendance, from a mean of 19·7% (SD 7·6) per cluster in the standard care group to 76·5% (20·0) in the HIVST plus financial incentive group (adjusted RR 2·84, 95% CI 2·37–3·41; table 4). The proportion of male partners starting ART, undergoing VMMC, or attending discordant couples' clinic was 168 (11·6%) of 1447 eligible women in the standard care group versus 309 (18·9%) of 1632 eligible women in the HIVST plus financial incentive group (pappendix p 3).

Table 4Clinic attendance and VMMC among male partners of women in the ANC cohort and HIV testing among sexual contacts of patients in the index cohort

Each trial arm had nine clusters. HIVST=HIV self-testing. ANC=antenatal care. RR=risk ratio. NA=not applicable. NM=not measured. VMMC=voluntary male medical circumcision.

For the secondary outcomes in the index cohort, the mean proportion per cluster of eligible sexual partners reported by the index patients as having tested for HIV within 28 days was higher in the HIVST only group and in the HIVST plus financial incentive group than in the standard care group (table 4). The number of sexual contacts attending the clinic for any HIV services was 51 (21·8%) of 234 eligible patients in the standard care group, 17 (10·1%) of 169 in the HIVST only group, and 181 (59·3%) of 305 in the HIVST plus financial incentive group. The number of sexual contacts who started ART, underwent VMMC, or attended discordant couples' clinic was 60 (19·7%) of 305 individuals in the HIVST plus financial incentive group as per intention-to-treat analysis, compared with 12 (5·1%) of 234 in the standard care group and 16 (9·5%) of 169 in the HIVST only group.

Only four (0·1%) of the 5252 individuals combined reported a marital separation related to self-testing at the day 28 interview; two in the HIVST only group and two in the HIVST plus financial incentive group, both of which were from the ANC cohort. No other adverse events were reported.

In the ANC cohort, differences in the primary outcome between each trial arm were more pronounced in the per-protocol analysis (table 3). The highest reported HIV testing coverage was in the HIVST only group. Results from an individual-level, random-effects logistic model were similar to those obtained from the cluster-level summaries approach for the ANC cohort primary outcome of male partner testing within 28 days (data not shown).

Among 863 sexual partners retested in the HIVST plus financial incentive group of both cohorts, HIVST sensitivity was 89·7% (95% CI 78·8–96·1) with 52 of 58 partners with HIV correctly identified through HIVST, and specificity was 99·5% (98·7–99·9), with 801 of 805 partners correctly identified as not having HIV through HIVST. Of the 52 true-positive patients newly diagnosed by HIVST, 20 were partners of HIV-negative women attending ANC and 32 were sexual contacts of index patients. There were an additional six false-negative, four false-positive, and 807 true-negative patients. All four false-positive results reflected misinterpretation of the kits showing negative results, whereas the six false-negative results were in patients with undetectable viral loads (<1000 copies per mL of blood).

In post-hoc analyses, we found that the proportion of male partners booked for VMMC among HIV-negative men (appendix p 3) and the proportion of male partners with new HIV diagnoses (table 4) were numerically higher in the HIVST plus financial incentive group than in the standard care group; however, the proportion of male partners booked for VMMC among all eligible women did not substantially differ between these two groups (table 4).Discussion

This pragmatic, cluster-randomised trial showed that routinely offering oral HIVST kits through secondary distribution could be readily integrated into routine clinical practice in rural health centres and district hospitals, with high participation and minimal harms. Secondary distribution provided a highly acceptable out-of-clinic strategy that substantially increased HIV testing by male partners of pregnant women, confirming high potential to contribute to elimination of mother-to-child transmission targets. In this first trial of HIVST for index testing, secondary distribution of kits from HIV testing clinics reached half (228 [48·1%]) of all 474 reported sexual contacts of people with newly diagnosed HIV. Study power was limited by low prevalence of undiagnosed HIV in Malawi and high clinic-level variability. However, additional research is needed to maximise accuracy from kits distributed by partners.

Secondary distribution of HIVST kits for pregnant women has consistently outperformed alternative approaches with regard to increasing HIV testing, and should now be considered regional best practice.4Choko AT Corbett EL Stallard N et al.HIV self-testing alone or with additional interventions, including financial incentives, and linkage to care or prevention among male partners of antenatal care clinic attendees in Malawi: an adaptive multi-arm, multi-stage cluster randomised trial., 5Masters SH Agot K Obonyo B Napierala Mavedzenge S Maman S Thirumurthy H Promoting partner testing and couples testing through secondary distribution of HIV self-tests: a randomized clinical trial., 6Thirumurthy H Masters SH Mavedzenge SN Maman S Omanga E Agot K Promoting male partner HIV testing and safer sexual decision making through secondary distribution of self-tests by HIV-negative female sex workers and women receiving antenatal and post-partum care in Kenya: a cohort study. HIV incidence during pregnancy and breastfeeding is well above rates in women who are not pregnant,18Chi BH Rosenberg NE Mweemba O et al.Involving both parents in HIV prevention during pregnancy and breastfeeding. making male partner testing and intensified HIV prevention a crucial part of strategies to eliminate mother-to-child transmission of HIV.