A cluster-randomised study in Zambia and Malawi has confirmed that patients with stable, non-complicated HIV infection are less likely to have gaps in their supply of antiretroviral therapy (ART) if they only visit their clinic and get their medication every six months instead of every three months or less.
The study found that 17.7% of patients who received the current standard of care in their clinics experienced a period of over 60 days without any ART during the year of the study. But this decreased to 13.6% in patients whose appointments were every three months and to 8.5% – less than half the rate – in those with six-monthly appointments. The researchers concluded that the inconvenience and cost of more frequent clinic visits meant that patients were more likely to miss appointments.
This study gives backing to recommendations from the World Health Organization and the President's Emergency Plan for AIDS Relief (PEPFAR), the world’s single biggest HIV funder, supporting six-monthly dispensing. However, a South African community response to PEPFAR's recommendations found that most people in South Africa were only getting their ART refills every one to three months and that, at the time of their report, six-monthly dispensing was non-existent.
A qualitative study in South Africa had found that patients favoured six-monthly dispensing and other randomised studies from Zimbabwe, Lesotho and South Africa have found quantitative improvements in adherence and retention. However, these three studies enhanced the six-monthly dispensing with support in the form of community refill clubs or adherence clubs, which use lay workers to educate patients and help them deal with the healthcare system.
The present study is the first to show improvements in retention in care and ART continuity in the large health clinics where most people get their ART. Additional support was given to clinics to help them to stick to three-monthly or six-monthly appointment intervals and to strengthen the ART supply chain, but the patients themselves did not receive additional support.
The INTERVAL study was conducted between May 2017 and April 2018 in 30 HIV clinics in Malawi and Zambia and 9118 patients were enrolled. To qualify for the study patients had to be on first-line ART, with an undetectable viral load for the previous six months, not need care for other conditions, and not be pregnant or breastfeeding. Of 14,430 patients initially screened, 37% of them were not eligible.
The clinics were split into three groups of ten, five in each country, and matched so each group had the same mix of large and small clinics and of geographical areas. In the first gruoup, no intervention was made and patients received the same standard of care as before. In the second, they received regular three-monthly check-ups and ART refills; in the third, six-monthly. The researchers looked to see if patients visited their clinics at other times for non-HIV-related issues and in fact very few did.
In the standard-of-care arm, most patients were receiving ART refills from once a month to every three months, though a few started getting six-monthly appointments during the study period. The most common dispensing interval in this group was in fact every three months and 59% of patients had a refill this often. However, they were not necessarily the same patients every time, and intervals varied. In the year before the study started, the average length of time between ART refills was nine weeks.
It’s therefore important to note that this study measured the improvements in ART continuity due to both greater regularity in appointments, by comparing the standard-of-care and three-monthly groups, and by lower frequency of appointments, by comparing the three-monthly and six-monthly groups.
The three groups were well-matched in terms of patient characteristics. The average age in all groups was 43, and two-thirds were women. Roughly 60% were married, about 30% widowed or separated, and 10% single. Most with a primary partner had disclosed their HIV status (a factor associated with higher adherence). They had been receiving ART for about five years on average. More than half had received no or only primary education, and only 15% had formal employment. But nearly half had some form of informal employment such as trading, and it is important for this study that nearly half had had to miss work in order to attend their clinic. The average journey time to the health facility was 40 minutes and time spent there was 2-3 hours.
One notable difference between the countries is that Malawi is significantly poorer than Zambia: the average monthly income of the Malawi patients was only US$27 compared with $128 in Zambia.
Compared to the standard-of-care group, and using relative rather than absolute differences, the three-monthly group were 23% less likely to have gaps of over 60 days in their ART, and the six-monthly group 52% less likely. The six-monthly group was 37% less likely to have gaps than the three-monthly group. The average time spent off ART in the year was respectively 36 days, 31 days and 18 days.
There was a bigger difference between the groups in Zambia than in Malawi, and the researchers are not sure why. In Zambia, the proportion who missed ART for more than 60 days in the standard-of-care, three-monthly and six-monthly groups was 25.4%, 17.7% and 10.3%, whereas in Malawi it was 10.3%, 8.8% and 6.8%. So since retention in the standard-of-care arm was better, maybe there was simply less room for improvement. The difference in Malawi between all groups was still statistically significant, however.
There were no differences by income or other variables. The men in the six-monthly group had a rather better improvement in retention than the women; they were 60% less likely to have more than 60 days off ART, and the women 48% less likely, than the standard-of-care group.
The benefits of less frequent appointments were only seen in patients who had been stable on ART for over a year. There was no statistical difference between the groups in patients who had been on stable ART for six to 12 months, though this was a small number of patients.
Costs for the healthcare system were also calculated in this study. The cost of ART and the overall number of pills dispensed was similar between all groups: since drug costs represent the greatest expense, this meant improvement in costs was largely driven by the cost of appointments, so was relatively modest, and confined to the six-monthly group. Excluding the costs of medications, the annual cost per patient in the six-monthly group was 33% lower in Malawi and 36% lower in Zambia than in the standard-of-care group.
Using simple cost-effectiveness calculations, the cost per patient of achieving fewer than 60 days off ART per year was only modestly different in Malawi ($90.76 in the six-monthly group versus $96.15 for standard of care) but considerably lower in Zambia ($142.41 versus $177.00).
In terms of costs borne by the patient, the researchers split the costs into costs due to lost work and transport costs. For the third of participants who spent money on travel, costs were lowest in the six-monthly group in both countries by more than 25%.
In terms of work lost, the Malawian patients lost an average of $3.98 in the six-monthly group and $5.30 in the standard-of-care group; in Zambia it was $9.98 and $15.00. Interestingly in Zambia, the cost both to clinic and to patient was slightly higher in the 3-monthly group than the standard-of-care group. This was probably because they spent more time at the clinic (three hours versus two hours) than standard-of-care patients; it’s not clear why, as the standard-of-care patients did not have any more non-ART-dispensing visits.
Limitations and conclusions
The differences in cost are relatively modest, but if implemented at scale, could save a considerable amount of money to be spent on other patients. The lower proportion of time spent off ART however is significant, with the six-monthly group less than half as likely to miss more than two months in a year than the standard-of-care group.
The study’s biggest limitation is that it didn’t measure whether less time off ART resulted in clinical improvements. The researchers had originally planned to have the proportion of patients who were virally suppressed as a secondary endpoint. However, although instituting annual viral-load testing for all patients is another PEPFAR goal, three-quarters of patients in either country did not have a scheduled viral load test done and so this endpoint could not be measured.
This study and the PEPFAR recommendations are reminders that many countries in Africa are now beginning to achieve percentages of adult patients diagnosed and linked to care that are within striking distance of the UNAIDS 90-90-90 target (which was supposed to have been reached at the end of last year). The proportion of patients achieving viral suppression is however lower than it is in the high-income world and often unknown – due to low rates of viral load testing.
In its absence, a gap of more than two months off ART is a quite strong predictor of virological failure, so moving to an appointment system that minimises this may improve the health and life expectancy of a significant number of patients.
Hoffman RM et al. Multimonth dispensing of up to six months of antiretroviral therapy in Malawi and Zambia (INTERVAL); a cluster-randomised, non-blinded, non-inferiority trial. Lancet Global Health 9:e628-638, May 2021 (open access).
Full image credit: 'Developing Infrastructure to Promote Quality Health Care'. Baylor College of Medicine Children's Foundation–Malawi / Robbie Flick. USAID images. Available at www.flickr.com/photos/usaid_images/14742507309/in/photolist-osKcNv under a Creative Commons licence CC BY-NC-ND 2.0. Image is for illustrative purposes only.