Evaluation of HIV treatment outcomes with reduced frequency of clinical encounters and antiretroviral treatment refills: A systematic review and meta-analysis

Abstract

Background: Global HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART.

Methods and findings: We searched databases​ between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults (≥16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97-1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75-1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98-1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63-3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa.

Conclusions: Based on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings.

Fig 1. PRISMA search results.

Fig 2. Retention in care: Reduced frequency versus 3-monthly clinical consultations among randomized or enrolled individuals.

(A) By study design. (B) By clinical consultation frequency. Goodrich 2021 had high withdrawal from the intervention (community-based care) arm; it was unclear if those who withdrew reengaged in care at the health facility. Fox 2019a and Fox 2019b were separated into an RCT and cohort design, respectively, based on the analysis described by the authors, where randomization was not preserved in the intervention arm in Fox 2019b. *Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; ND, not described; P, pharmacy; RCT, randomized controlled trial; RF, reduced frequency; RR, risk ratio.

Fig 3. Retention in care: Reduced frequency versus 6-monthly clinical consultations.

*Cluster-adjusted RR. 6 MO, 6-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; RF, reduced frequency; RR, risk ratio.

Fig 4. Viral suppression: Reduced frequency versus 3-monthly clinical consultations, by study design.

(A) Among those randomized or enrolled. (B) Among those with viral load testing. Fox 2019a and Fox 2019b were separated into an RCT and cohort design, respectively, based on the analysis described by the authors, where randomization was not preserved in the intervention arm in Fox 2019b. *Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; ND, not described; P, pharmacy; RCT, randomized controlled trial; RF, reduced frequency; RR, risk ratio.

Fig 5. Viral suppression: Reduced frequency versus 6-monthly clinical consultations.

(A) Among those randomized. (B) Among those with viral load testing. *Cluster-adjusted RR. 6 MO, 6-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; RF, reduced frequency; RR, risk ratio.

Fig 6. Mortality: Reduced frequency versus 3-monthly clinical consultations among randomized or enrolled individuals.

(A) By study design. (B) By clinical consultation frequency. *Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; P, pharmacy; RCT, randomized controlled trial; RF, reduced frequency; RR, risk ratio.

Fig 7. Mortality: Reduced frequency versus 6-monthly clinical consultations.

*Cluster-adjusted RR. 6 MO, 6-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; RF, reduced frequency; RR, risk ratio.

Fig 8. Retention in care: Reduced frequency versus 3-monthly antiviral treatment refills.

*Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; RF, reduced frequency; RR, risk ratio.

Fig 9. Viral suppression: Reduced frequency versus 3-monthly antiviral treatment refills, by study design.

(A) Among those randomized. (B) Among those with viral load testing. *Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; P, pharmacy; RF, reduced frequency; RR, risk ratio.

Fig 10. Mortality: Reduced frequency versus 3-monthly refills.

*Cluster-adjusted RR. 3 MO, 3-monthly; AC, adherence club; Comm, community; e, number of events; n, number of participants; P, pharmacy; RF, reduced frequency; RR, risk ratio.