Michael H. Chung

Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial

BACKGROUND Mobile (cell) phone communication has been suggested as a method to improve delivery of health services. However, data on the effects of mobile health technology on patient outcomes in resource-limited settings are limited. We aimed to assess whether mobile phone communication between health-care workers and patients starting antiretroviral therapy in Kenya improved drug adherence and suppression of plasma HIV-1 RNA load. METHODS WelTel Kenya1 was a multisite randomised clinical trial of HIV-infected adults initiating antiretroviral therapy (ART) in three clinics in Kenya. Patients were randomised (1:1) by simple randomisation with a random number generating program to a mobile phone short message service (SMS) intervention or standard care. Patients in the intervention group received weekly SMS messages from a clinic nurse and were required to respond within 48 h. Randomisation, laboratory assays, and analyses were done by investigators masked to treatment allocation; however, study participants and clinic staff were not masked to treatment. Primary outcomes were self-reported ART adherence (>95% of prescribed doses in the past 30 days at both 6 and 12 month follow-up visits) and plasma HIV-1 viral RNA load suppression (<400 copies per mL) at 12 months. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00830622. FINDINGS Between May, 2007, and October, 2008, we randomly assigned 538 participants to the SMS intervention (n=273) or to standard care (n=265). Adherence to ART was reported in 168 of 273 patients receiving the SMS intervention compared with 132 of 265 in the control group (relative risk [RR] for non-adherence 0·81, 95% CI 0·69-0·94; p=0·006). Suppressed viral loads were reported in 156 of 273 patients in the SMS group and 128 of 265 in the control group, (RR for virologic failure 0·84, 95% CI 0·71-0·99; p=0·04). The number needed to treat (NNT) to achieve greater than 95% adherence was nine (95% CI 5·0-29·5) and the NNT to achieve viral load suppression was 11 (5·8-227·3). INTERPRETATION Patients who received SMS support had significantly improved ART adherence and rates of viral suppression compared with the control individuals. Mobile phones might be effective tools to improve patient outcome in resource-limited settings. FUNDING US Presidents Emergency Plan for AIDS Relief.

A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes

Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.

HIV-1 persists in breast milk cells despite antiretroviral treatment to prevent mother-to-child transmission.

Background:The effects of short-course antiretrovirals given to reduce mother-to-child transmission (MTCT) on temporal patterns of cell-associated HIV-1 RNA and DNA in breast milk are not well defined. Methods:Women in Kenya received short-course zidovudine (ZDV), single-dose nevirapine (sdNVP), combination ZDV/sdNVP or short-course highly active antiretroviral therapy (HAART). Breast milk samples were collected two to three times weekly for 4–6 weeks. HIV-1 DNA was quantified by real-time PCR. Cell-free and cell-associated RNA levels were quantified by the Gen-Probe HIV-1 viral load assay. Results:Cell-free HIV-1 RNA levels in breast milk were significantly suppressed by sdNVP, ZDV/sdNVP or HAART therapy compared with ZDV between day 3 and week 4 postpartum (P ≤ 0.03). Breast milk HIV-1 DNA levels (infected cell levels) were not significantly different between treatment arms at any timepoint during the 4–6-week follow-up. At 3 weeks postpartum, when the difference in cell-free RNA levels was the greatest comparing HAART directly with ZDV (P = 0.0001), median log10 HIV-1 DNA copies per 1 × 106 cells were 2.78, 2.54, 2.69, and 2.31 in the ZDV, sdNVP, ZDV/sdNVP and HAART arms, respectively (P = 0.23). Cell-associated HIV-1 RNA levels were modestly suppressed in HAART versus ZDV/sdNVP during week 3 (3.37 versus 4.02, P = 0.04), as well as over time according to a linear mixed-effects model. Conclusion:Cell-free and, to a lesser extent, cell-associated HIV-1 RNA levels in breast milk were suppressed by antiretroviral regimens used to prevent MTCT. However, even with HAART, there was no significant reduction in the reservoir of infected cells, which could contribute to breast milk HIV-1 transmission.

Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine

Objective:To compare the effect of perinatal regimens of short-course nevirapine (HIVNET 012) and zidovudine [Thai-Centers for Disease Control and Prevention (CDC) regimen] on breast milk viral shedding and perinatal transmission during the first 6 weeks postpartum in a randomized clinical trial. Design:Randomized clinical trial. Methods:Pregnant HIV-1 seropositive women in Nairobi, Kenya who planned to breastfeed were randomized to HIVNET 012 or Thai-CDC regimens. Two to four breast milk samples were collected each week between delivery and 6 weeks postpartum. Breast milk HIV-1 RNA was quantified using the Gen-Probe TMA assay. Infants were tested for HIV-1 DNA at birth and 6 weeks. Results:From March to October 2003, 76 women were enrolled and 795 breast milk samples were collected from 60 women who were randomized and followed after delivery. Between 3 and 21 days postpartum, nevirapine was associated with significantly greater suppression of breast milk log10 HIV-1 RNA: days 3 to 7 (1.98 versus 2.42, P = 0.1); days 8 to 14 (1.78 versus 2.48, P = 0.005); days 15 to 21 (1.90 versus 2.97, P = 0.003). At 6 weeks, the HIV-1 perinatal transmission rate was significantly lower among those who took nevirapine than zidovudine (6.8% versus 30.3%, P = 0.02). Conclusions:Compared to a peripartum zidovudine regimen, nevirapine was significantly more likely to decrease HIV-1 RNA in breast milk during the first week and through the third week postpartum following single-dose administration, and corresponded with decreased transmission risk at 6 weeks. Sustained breast milk HIV-1 suppression may contribute to the ability of nevirapine to decrease perinatal transmission of HIV-1.

Implementation of free cotrimoxazole prophylaxis improves clinic retention among antiretroviral therapy-ineligible clients in Kenya.

Objective:To determine whether implementation of free cotrimoxazole (CTX) provision was associated with improved retention among clients ineligible for antiretroviral therapy (ART) enrolled in an HIV treatment program in Kenya. Design:Data were obtained from a clinical cohort for program evaluation purposes. Twelve-month clinic retention was compared among ART-ineligible clients enrolled in the time period before free CTX versus the time period after. Methods:Statistical comparisons were made using Kaplan–Meier survival curves, log-rank tests, and multivariate Cox proportional hazards models. To exclude potential temporal program changes that may have influenced retention, ART clients before and after the same cut-off date were compared. Findings:Among adult clients enrolled between 2005 and 2007, 3234 began ART within 1 year of enrollment, and 1024 of those who did not start treatment were defined as ART-ineligible. ART-ineligible clients enrolled in the period following free CTX provision had higher 12-month retention (84%) than those who enrolled prior to free CTX (63%; P < 0.001). Retention did not change significantly during these periods among ART clients (P = 0.55). In multivariate analysis, ART-ineligible clients enrolled prior to free CTX were more than twice as likely to be lost to follow-up compared to those following free CTX [adjusted hazard ratio (aHR) = 2.64, 95% confidence interval 1.95–3.57, P < 0.001]. Conclusion:Provision of free CTX was associated with significantly improved retention among ART-ineligible clients. Retention and CD4-monitoring of ART-ineligible clients are essential to promptly identify ART eligibility and provide treatment. Implementation of free CTX may improve retention in sub-Saharan Africa and, via increasing timely ART initiation, provide survival benefit.

In-depth analysis of patient-clinician cell phone communication during the WelTel Kenya1 antiretroviral adherence trial.

Background The WelTel Kenya1 trial demonstrated that text message support improved adherence to antiretroviral therapy (ART) and suppression of HIV-1 RNA load. The intervention involved sending weekly messages to patients inquiring how they were doing; participants were required to respond either that they were well or that there was a problem. Objectives 1) Describe problems participants identified through mobile phone support and reasons why participants did not respond to the messages; 2) investigate factors associated with indicating a problem and not responding; and 3) examine participant perceptions of the intervention. Design Secondary analysis of WelTel Kenya1 trial data. Methods Reasons participants indicated a problem or did not respond were extracted from the study log. Negative binomial regression was used to determine participant characteristics associated with indicating a problem and non-response. Data from follow-up questionnaires were used to describe participant perceptions of the intervention. Results Between 2007 and 2009, 271 participants generated 11,873 responses; 377 of which indicated a problem. Health issues were the primary reason for problem responses (72%). Rural residence (adjusted incidence rate ratio [IRR] 1.96; 95%CI 1.19–3.25; p = 0.009 and age were associated with indicating a problem (adjusted IRR 0.63 per increase in age group category; 95%CI 0.50–0.80; p<0.001). Higher educational level was associated with a decreased rate of non-response (adjusted IRR 0.81; 95%CI 0.69–0.94; p = 0.005). Of participants interviewed, 62% (n = 129) stated there were no barriers to the intervention; cell phone issues were the most common barrier. Benefits included reminding patients to take medication and promoting a feeling that “someone cares”. Conclusions The WelTel intervention enabled frequent communication between clinicians and patients during the WelTel Kenya1 trial. Many patients valued the service for the support it provided, with health-related concerns comprising the majority of problems identified by participants. Few sociodemographic characteristics were associated with participant engagement in the intervention.

Younger age at HAART initiation is associated with more rapid growth reconstitution

Objectives:Patterns of growth following highly active antiretroviral therapy (HAART) administration among children are not well defined. The objective of this study was to determine rates and predictors of growth reconstitution among children on HAART. Methods:A study was conducted among HIV-1-infected children initiating HAART at an HIV treatment clinic in Kenya. Kaplan–Meier survival curves and Cox proportional hazards regression models compared catch-up growth (Z-score ≥0) at 12 months post-HAART. Multivariate linear mixed-effects models determined rates and predictors of growth following HAART. Results:One hundred and seventy-three HIV-1-infected children initiated HAART with a median age of 4.7 years [interquartile range (IQR) 2.4, 7.0]. At baseline, children below 3 years had lower weight-for-age (WAZ) and weight-for-height (WHZ) Z-scores than children 3–5 and 6–10 years (WAZ: P = 0.03; WHZ: P = 0.006). Adjusting for baseline growth, children below 3 years were two to three-fold more likely to attain population age-norms (Z-score = 0) than 6–10 years (WAZ: P = 0.055; WHZ: P = 0.005) at 12 months post-HAART. After adjustment, children below 3 years had higher increases in WAZ and WHZ following HAART than 6–10 years (WAZ: P = 0.006; WHZ: P = 0.005). Children at WHO stage at least 3 at baseline experienced more rapid WHZ reconstitution (P = 0.002). Food supplementation while on HAART was associated with increased monthly gains in weight indices (WAZ: P = 0.001; WHZ: P = 0.005), and multivitamins were associated with greater increases in height (P < 0.01). Conclusion:Following HAART initiation, younger children had more rapid catch-up to the population-average weight of their peers than older children, demonstrating growth benefit of earlier HAART. In addition to HAART, food supplementation and multivitamins may also accelerate growth reconstitution.

Lower Risk of Resistance After Short-Course HAART Compared With Zidovudine/Single-Dose Nevirapine Used for Prevention of HIV-1 Mother-to-Child Transmission

Background:Antiretroviral resistance after short-course regimens used to prevent mother-to-child transmission has consequences for later treatment. Directly comparing the prevalence of resistance after short-course regimens of highly active antiretroviral therapy (HAART) and zidovudine plus single-dose nevirapine (ZDV/sdNVP) will provide critical information when assessing the relative merits of these antiretroviral interventions. Methods:In a clinical trial in Kenya, pregnant women were randomized to receive either ZDV/sdNVP or a short-course of HAART through 6 months of breastfeeding. Plasma samples were collected 3-12 months after treatment cessation, and resistance to reverse transcriptase inhibitors was assessed using both a sequencing assay and highly sensitive allele-specific polymerase chain reaction assays. Results:No mutations associated with resistance were detectable by sequencing in either the ZDV/sdNVP or HAART arms at 3 months posttreatment, indicating that resistant viruses were not present in >20% of virus. Using allele-specific polymerase chain reaction assays for K103N and Y181C, we detected low levels of resistant virus in 75% of women treated with ZDV/sdNVP and only 18% of women treated with HAART (P = 0.007). Y181C was more prevalent than K103N at 3 months and showed little evidence of decay by 12 months. Conclusions:Our finding provides evidence that compared with ZDV/sdNVP, HAART reduces but does not eliminate nevirapine resistance.

The consequences of post-election violence on antiretroviral HIV therapy in Kenya

Abstract Over 1000 individuals were killed and 600,000 were displaced during post-election violence (PEV) in Kenya in 2008. Antiretroviral therapy (ART) depends on continuous access to medications which may have been interrupted due to PEV. In a mixed-methods retrospective review, treatment interruption of ART during PEV was measured among 2534 HIV-positive adults attending the Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. Clients experiencing treatment interruption were compared between the PEV period (30 December 2007 to 28 February 2008) and the same time period one year earlier. Treatment interruption was defined as visiting the pharmacy ≥48 hours after antiretrovirals were calculated to have been completed. Despite clinical services remaining open throughout the PEV period, more clients (16.1%) experienced treatment interruption than during the comparison period (10.2%). Mean daily pharmacy visits were significantly lower (87 vs. 104; p < 0.006) and more variable (p = 0.03) during PEV. Among clients present at both periods (n = 1605), the odds of treatment interruption were 71% higher during PEV (95% confidence interval [CI], 34–118%). In multivariate analysis, men (odds ratio [OR], 1.37; 95% CI, 1.07–1.76) and clients traveling ≥3 hours to clinic (OR, 1.86; 95% CI, 1.28–2.71) were significantly more likely to experience treatment interruption. Clients affected by PEV were interviewed about factors associated with treatment interruption using semi-structured methods. Clients described fear, lack of transportation, and violence as contributing to treatment interruption. Widespread violence associated with the 2007 election in Kenya revealed the dependence of HIV patients on a stable civil society and infrastructure to access medications. Without the ability to maintain consistent HIV therapy, some patients face rapid treatment failure. HIV programs should have appropriate contingency plans wherever political instability may occur. Peace may be one of the most effective and most important public health interventions in Africa.

HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis

Summary Background Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs. Methods This study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions. Findings We identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5–15·9) in southern Africa, 10·1% (5·1–19·4) in eastern Africa, 7·2% (2·9–16·5) in western and central Africa, and 9·4% (6·6–13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16–29) in southern Africa, 17% (5–30) in eastern Africa, 17% (6–29) in western and central Africa, 11% (5–18) in Latin America and the Caribbean, and 11% (2–20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa. Interpretation Pretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHOs 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition. Funding Bill & Melinda Gates Foundation and World Health Organization.