Possible initial regimens

The World Health Organisation has defined the following combinations as preferable initial regimens for resource-limited countries:

• AZT/3TC (zidovudine/lamivudine) or d4T/3TC (stavudine/lamivudine) + nevirapine or efavirenz or nelfinavir

• AZT/3TC/abacavir (Trizivir) - although this is rarely used, because even the concessionary pricing offered by GSK does not compete with generic alternatives and because clinical trials have now demonstrated the clear inferiority of this triple nucleoside combination to those which include an NNRTI or a ritonavir-boosted protease inhibitor.

• AZT/ddI (zidovudine/didanosine)- may be best reserved for second line use after failure of d4T/3TC treatment

• ddI/3TC - less studied, cannot be combined conveniently with nelfinavir due to food restrictions (ddI on empty stomach and nelfinavir with food)

• Two nucleoside analogues plus low dose ritonavir plus saquinavir or indinavir plus low dose ritonavir or lopinavir/ritonavir

Recently presented evidence suggests that d4T is more strongly associated with fat wasting (lipoatrophy) than AZT. See Choosing a nucleoside or nucleotide reverse transcriptase inhibitor backbone in Anti-HIV therapy: Choosing a combination for further discussion of this issue. This still has to be set against the risk of anaemia when AZT is used in a population with advanced HIV disease, where the availability of reliable diagnosis and safe, affordable treatment may be limited.

Advantages of standardised regimens

Potential advantages of the use of standardised regimens in resource-limited settings include:

• Simplified training and education of providers and patients

• Simplified monitoring for toxicity

• Predictable patterns of resistance

• Predictable and standardised sequence of drug combinations, assisting mass procument and prescribing

• Simplified education on adherence and easier organisation of support groups, when everyone faces the same challenges from a particular regimen

• Limited number of drugs to procure and manage

Practical experience with standardised regimens

MSF-Switzerland has had two ARV programmes, in Yaounde (Cameroon) and Guatemala City, which enrolled 100-150 people each. AZT/3TC/nevirapine was chosen as the initial regimen, and 70% of those treated with it had viral load below 100 copies/mm³ after 6 months. Simplification of the protocols used in ARV treatment programmes is a matter of urgency to respond to the number of people awaiting treatment, according to the doctors at these centres. (Calmy).

The US Centers for Disease Control have an initiative to develop standardised treatment approaches to enable larger-scale ARV provision in countries with limited resources. Initial programmes in Uganda, Cote d'Ivoire and Kenya, while successful in keeping some people alive, had so far transferred very individualised approaches to the use of ARVs, supported by high levels of laboratory monitoring, in ways that did not lend themselves to being scaled up much further (Lackritz).

The proposed framework includes standardised treatment regimens, standardised criteria for initiating and changing therapy, and simplified laboratory monitoring using alternatives to present-day, high-cost, CD4 and viral load tests. Comprehensive programmes would also need to include patient and community education, social support, adherence [support] and linkages to HIV prevention [work].

The criteria for choice of suitable regimens should include drug cost, availability, efficacy, toxicity, dosing schedules [once or twice daily without food restrictions], refrigeration [no need for], safety during pregnancy and compatibility with tuberculosis medications.

Standardising on fixed dose combinations

Putting a triple regimen into one tablet or capsule, where the respective doses and chemistry allow, can radically simplify the use of ARVs. The options available are discussed further under the heading of 'Generic antiretrovirals' since, at present, viable fixed dose combinations can generally only be provided by generic manufacturers.

Ironically, this may mean that people in some limited resource settings have a better and more manageable treatment option than many people in wealthier countries.

Initial published experience in the use of these combinations has mostly centred on a product called 'Triomune' from the Indian company Cipla, which consists of nevirapine, d4T (with two dosage options, 30mg and 40mg), and 3TC. A combination of nevirapine, AZT and 3TC has also been marketed in India.

Doctors and researchers working at two clinics, in Ahmedabad and Pune, have recruited ARV-naﶥ patients starting on either of these fixed dose combinations into an observational cohort, and have reported on five-month follow-up (Pujari). After an initial lead-in period (normally two weeks) when drugs were given separately to allow dose-escalation of the nevirapine, 659 patients started on d4T/3TC/NVP and 335 started on AZT/3TC/NVP. The majority of the patients were male (which says more about access to money to pay for treatment than the epidemiology of HIV in India).

Patients were seen at monthly clinic visits and given CD4 counts every 3-6 months. Adverse events (particularly, those thought by the investigators to be linked to nevirapine) and adherence (as reported by the patient) were recorded.

Out of 994 patients studied, 726 (78.3% male and 21.7% female) who had completed minimum of 3 months were evaluable. 15.8% of patients were lost to follow-up or had CD4 decline after 3 months. Adverse events were documented in 23.2%, usually occurring within the first 12 weeks of initiating therapy. Rash was documented in 6.9% (10; 9 SJS and 1 fatal), GI disturbances in 15.6% and hepatitis (symptomatic, clinical) in 3.3%. Being female was significantly associated with development of AE, however age, baseline CD4 counts and concomitant co-trimoxazole were not.

Mean CD4 counts at baseline, 3 mo, 6 mo, 9 mo, 12 mo, 18 mo and 24 mo were 125.6 (119.8-131.3, n=726), 281.2 (270.5-291.8, n=726), 310.8 (298.1-323.5, n=619), 349.9 (328.5-371.2, n=256), 380.6 (358.4-402.9, n=332), 422.8 (380.3-465.3, n=124) and 403.8 (326.6-481.1, n=33) respectively. In patients showing improvement more than 95% of the doses were taken regularly.

The fixed dose combinations of NVP-based HAART showed good safety and durable immunological improvement.

Disadvantages of standardised regimens

From the viewpoint of resource-rich countries, the disadvantages of standardised regimens are many. However, these arguments are largely irrelevant if a country or individual does not have the resources to afford flexibility.

From experience with national policies on malaria treatment, there is likely to be a major problem of institutional and professional inertia, when the time comes to change to a new first-line treatment. This may be needed because the first choice has lost efficacy due to acquired resistance or because a more effective, tolerable and easily delivered regimen has become available.

Dual therapy or triple therapy in resource-limited settings?

The cost of antiretrovirals therapy has led to the use of dual nucleoside analogue (NRTI) treatment, notably in Thailand, although as the cost of triple therapy has come down this is increasingly rejected. Dual NRTI therapy is considered sub-optimal in the North because, although it has shown clinical benefit when compared with AZT alone, it is less effective than triple combination therapy, and leads to the development of resistance to NRTIs due to incomplete control of viral replication.

However, the debate about dual versus triple therapy is based on data gathered more than six years ago, and the nucleosides available were AZT (zidovudine), 3TC (lamivudine), ddC (zalcitabine) and ddI (didanosine). In recent years several new options have emerged, and the strategy of dual therapy may be worth revisiting.

An argument has been made, for example, that the 'genetic barrier to resistance' - the number of different mutations that are needed, for the virus to become resistant to one drug - varies widely between drugs. In the case of ritonavir-boosted lopinavir, for example, resistance may need multiple mutations. It can be argued that makes it the equivalent of a combination of other drugs. Lopinavir/ritonavir is not ideal for use in resource-limited settings for reasons of transport and storage. Two of the other 'high barrier' drugs - didanosine (dd1) and tenofovir (TDF) may be better not combined with each other, since TDF boosts the levels of ddI and greatly increases the risks of its side effects.

A one log reduction in viral load (from 100,000 copies/ml to 10,000 copies/ml for example) after eight weeks of dual NRTI therapy was associated with a 50% reduction in the risk of developing AIDS over 96 weeks of follow-up in the Delta study. (There is a discussion of the clinical benefit of different levels of viral load reduction in Monitoring treatment with viral load in Viral load, CD4 cell counts and other tests: Viral load). However, subsequent trials and large cohort studies have shown that triple therapy is associated with a significantly greater reduction in the risk of AIDS or death when compared with dual therapy.

References

Calmy A et al. From pilot projects to extended ARV programs; an MSF experience. XIV International AIDS Conference, Barcelona, abstract ThOrF1519, 2002.

Lackritz EM et al. Next steps for expanding access to antiretroviral therapy in resource-restricted settings. XIV International AIDS Conference, Barcelona, abstract ThOrF1515, 2002.

Pujari S et al. Safety and immunological effectiveness of simplified fixed-dose combination of nevirapine-based HAART amongst Indian patients: extended follow-up data. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 110, 2003.

Weidle PJ et al. HIV/AIDS treatment and HIV vaccines for Africa. The Lancet 359: 2261-2267, 2002.

World Health Organisation. Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach (draft). WHO, 2002.