STIs in resource limited settings
Ben Cheng and Polly Clayden for HIV i-Base
Late breakers at the13 International Conference on AIDS and STIs in Africa (ICASA) in September included early data from two ongoing structured treatment interruption trials in Africa presented by Cissy Kityo [1,2].
Intermittent therapy study in Uganda
This randomised controlled trial is to evaluate the effects of continuous HAART versus two intermittent approaches – seven days on/seven days off and five days on/two days off therapy – the study rationale being that this could reduce both cost and toxicities and have a practical role in developing countries.
Recruitment began in January 2003; the goal is to enrol 171 individuals (57 in each arm). The duration of the study is 72 weeks with six-weekly evaluation. The primary endpoint is the proportion of patients in each arm with viral load of <50 copies/ml3 at 72 weeks. Secondary endpoints include CD4 evaluation, laboratory evaluation of toxicities and reasons for change of therapy.
Inclusion criteria are as follows: patients must be on continuous HAART (2 NRTIs plus PI or efavirenz) for >90 days at enrolment with viral load of <50 copies/mL at baseline and CD4 >125 cells/mm3 within 30 days before randomisation. If CD4 count is <200 cells/mm3, patients must be receiving PCP prophylaxis, they should not be on a salvage regimen or receiving experimental antiretrovirals for >6 months (hydroxyurea allowed), nevirapine or abacavir.
And study termination criteria include: viral load >1000 copies/mL on two consecutive measurements, viral load >10,000 copies/mL on one single measurement, CD4 drop of >30% on two consecutive measurements, CD4 <100 cells/mm3, malignancy (excluding MC-KS), serious HIV illness and permanent discontinuation of antiretrovirals.
As of September 116 patients have been screened (56% women) and 69 have enroled and completed 12 weeks of the study (53% women). Median CD4 count is 261 cells/mm3 (mean 256 cells/mm3), with 69% having CD4 >200 cells/mm3. A total of 61% of patients are receiving d4T+3TC+efavirenz and 31% AZT+3TC+efavirenz.
Dr Kityo reported that of the 69 patients who have reached week 12, those with baseline CD4 >200 cells/mm3 on either of the intermittent treatment arms had a slight trend to have decreasing CD4 counts but their viral loads still remained undetectable. Those on either intermittent treatment arms with <200 CD4 cells/mm3 at baseline had a trend of increasing CD4 counts but this was less than those receiving continuous HAART.
There were five virologic failures: three using continuous HAART and two using interrupted therapy – one on the 7/7 arm (in a patient who did not take their d4T) and one on the 5/2 arm (who did not follow protocol).
There were no adverse events data presented. Dr Kityo reported that there have been some problems with adherence on the continuous arm because some of the individuals know that SIT may be a treatment strategy.
She concluded that these preliminary results show that short cycle intermittent therapy has maintained suppression of viral load while preserving CD4 counts in a small sample of patients, and that results are similar for patients with CD4 counts above and below 200 cell/mm3.
One of the issues that came up during the question/discussion period was the six weeks monitoring. If the study is to look for a ‘cheaper’ ARV strategy, then the rigorous monitoring adds a huge financial burden.
Development of antiretroviral therapy in Africa (DART) study
The aim of the DART study, which also began enrolment in January this year, is to compare routine laboratory and clinical monitoring (LCM) versus clinical monitoring only (CMO). A second randomisation will access the risk and benefits of structured treatment interruption (three months on /three months off) or continuous therapy for those with CD4 >200 cells/mm3 after 24 weeks of HAART.
A pilot study involving 100 patients for the STI randomisation is built into the protocol in which 3,000 patients will receive triple therapy. The first-line regimen is AZT/3TC (Combivir) plus tenofovir and some patients will receive Combivir plus nevirapine. Second-line regimen is two NRTIs plus a boosted PI or nevirapine. Viral loads will be performed retrospectively and the results will not be provided in real time in this study.
The study is being conducted at two sites in Uganda and one site in Zimbabwe. Additionally, the Academic Alliance in Uganda is a satellite site. Follow up is four to five years.
As of 9 September 2003, 1,969 patients have been screened and 985 have been randomised to the first part of the study. The first patient to start the STI pilot study did so on 28 July 2003.
Baseline characteristics are: median age 37.2 years with 17% > 45 years median CD4 85 cells/mm3 (18% <25 CD4, 32% <50 CD4, 53% WHO stage 3, 19% WHO stage 2). Sixty-seven per cent of patients are women of which 14 individuals had previously received single dose nevirapine for mother to child transmission prophylaxis.
The study design is:
|3000 patients WHO stage 2, 3 or 4; CD4 <200 cells/mm3|
|(N = 15000)||(N = 15000)|
|week 24/48 (2nd randomisation)|
Dr Kityo reported a median change in CD4 cell counts after 24 weeks of 120 cells/mm3. Seven patients substituted d4T for AZT due to anaemia.
A decision about whether the second randomisation to the STI arm will be included will be made in early 2004 after results from the pilot STI phase are analysed. A similar trial to DART but for children and adolescents is being planned.
The investigators anticipate that: “The DART study will assess whether laboratory monitoring is necessary for effective ART use, and whether toxicity can be reduced by STI without compromising efficacy.”
Although it is laudable to see a trial that will roll out to substantial numbers of African people, we are simultaneously seeing disappointing results with similar stop and start strategies reported from the “Staccato” and National Institutes of AIDS and Infectious Diseases (NIAID) studies reported on pages 17-18.
There are many outstanding questions for such strategies, notably resistance, complexities of adherence and, in this population particularly, stopping and starting therapy in people with very low baseline CD4 at initiation.
- Kityo C and Mugyenyi PN. A randomised controlled trial of short cycle intermittent versus continuous HAART for the treatment of chronic HIV infection in Uganda. Programme and abstracts 13th ICASA. Nairobi 21–26 September 2003. Abstract 1098929.
- Kityo C. A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa: The DART trial. Programme and abstracts 13thICASA. Nairobi 21–26 September 2003. Abstract 1098933.
Further reports (many non-medical) from this conference are at: