Advisory panel members include Dr. Vijay Anthony Prabhu (Chennai, India), and Desmond Martin (President, Southern Africa HIV Clinicians Society); they both provide commentary in this article.
Fixed-dose combination antiretrovirals (FDC ARVs) are products that combine two or more active drugs in one tablet or capsule. In many countries, they now offer the cheapest available route to a complete and effective ARV regimen. There are many potential advantages of using FDCs. The most obvious are the simplification of what is supplied to and taken by individual patients and reduced potential for inappropriate sharing of drugs.
In a managed healthcare system where costs are shared, as is planned in Thailand, these drugs can free up resources to provide more expensive second- and third-line treatment options to those who need them, which is a universal benefit. Standardization of first-line regimens carries further potential benefits, including the development of simple education packages for healthcare workers and community members and possible economies of scale in laboratory monitoring tests.
Limitations at present include the lack of pediatric equivalents, inadequate provision for lead-in dosing and a number of other shortcomings concerning availability, packaging and provision for reporting adverse events.
This may be the right way to go for large-scale treatment programs, but there is still a distance to be traveled before the products are fully suited to that purpose.
Quality Issues and Availability
WHO's Essential Drugs and Medicines team has established a project to document the procedures and certification of generic facilities used to produce medicines for HIV and AIDS treatment that are not registered with the U.S. Food and Drug Administration (FDA) or European drug regulatory agencies recognized by the European Medicines Evaluation Agency (EMEA).
The Global Fund to fight AIDS, TB and Malaria has signaled that they will rely on this WHO list as a basis for approving the purchase of generic ARVs and other medicines, so the inclusion of products and of their makers on the list may have an increasing influence on their availability.
The Indian companies Cipla and Ranbaxy already have ARVs on the list; Hetero and Aurobindo products are being assessed. However, most of the products named are not listed by WHO. Ranbaxy's AZT/3TC is the one exception.
The Thai Government Pharmaceutical Organization makes drugs primarily for domestic use, with a high level of attention to quality control. It is supplying them in limited quantities to Cambodia, Sri Lanka and Laos, and has recently agreed to supply them to Indonesia. It is also supporting a number of African countries in establishing local manufacturing. Argentina, Brazil, China, Mexico and Vietnam are producing generic antiretrovirals, but with the exception of some AZT/3TC, these do not seem to include fixed dose combination products of the kind discussed here.
Fixed-Dose Products Now Available
AZT 300 mg + 3TC 150 mg + NVP 200 mg
DUOVIR-N (Cipla Ltd)
ZIDOVEX-L-N (Imunus Aurobindo)
For lead-in dosing (or if NVP must be stopped):
AZT 300 mg + 3TC 150 mg -- use separate drugs, or:
DUOVIR (Cipla Ltd)
VIROCOMB (Ranbaxy Laboratories Ltd)
ZIDOLAM (Genix Pharma/Hetero)
d4T 30 mg + 3TC 150 mg + NVP 200 mg
GPO-VIR S 30 (Thai Government Pharmaceutical Organization)
STAVEX-30 LN (Imunus Aurobindo)
TRIOMUNE-30 (Cipla Ltd)
VIROLANS [capsules, d4T 30 mg version] (Ranbaxy Laboratories Ltd)
For lead-in dosing (or if NVP must be stopped):
d4T 30 mg + 3TC 150 mg -- use separate drugs, or:
LAMISTAR 30 (Genix Pharma/Hetero)
LAMIVIR-S-30 (Cipla Ltd)
VIROLIS [capsules, d4T 30 mg version] (Ranbaxy Laboratories Ltd)
d4T 40 mg + 3TC 150 mg + NVP 200 mg
GPO-VIR S 40 (Thai Government Pharmaceutical Organization)
TRIOMUNE-40 (Cipla Ltd)
VIROLANS [capsules, d4T 40 mg version] (Ranbaxy Laboratories Ltd)
For lead-in dosing (or if NVP must be stopped):
d4T 40 mg + 3TC 150 mg -- use separate drugs, or:
LAMISTAR 40 (Genix Pharma/Hetero)
LAMIVIR-S-40 (Cipla Ltd)
VIROLIS [capsule, d4T 40 mg version] (Ranbaxy Laboratories Ltd)
All of the medicines listed above are taken as one tablet, twice daily (12 hour intervals), with or without food.
Whatever the drug combination used, its success for an individual patient will depend on the ability of that person to take it consistently as prescribed.
Where patients are paying for their own treatment as in Kampala, inability to maintain those payments has emerged as the main reason for breaks in treatment, as reported at the 10th Retrovirus Conference in Boston by Byahihi-Tusiime. While the treatments discussed here are priced as low as $35 a month, they are still a long way from being affordable by most people with HIV. In Uganda, Molly Tumusiime reports there have been times when people went short of food to pay for ARVs, or missed out on ARVs to pay for monitoring tests. This is a powerful case for subsidizing treatment to make it genuinely affordable, as has been done in Senegal's pioneering treatment access program (described in Boston by Dr. Salif Sow) -- and as is planned in Thailand.
Failing that, the strategy reported by YRG-CARE in India, of careful and thorough discussion with patients of their financial circumstances before starting on treatment may be helpful to some. However, this is a difficult role for hard-pressed clinical staff to assume. There has to be a limit to the clinic's responsibility, to ensure that the patient understands what treatment they need and how much it costs, and is able to access any support or discounts that may be available to them. Beyond that, it must be a decision for the patient themselves and their family.
Dr. Prabhu: ARV therapy has come a long way in India. The financial burden has steadily decreased and remains at around $35 per month for fixed-dose combination triple ARV therapy. The pricing of these potent drugs has received widespread publicity. Generic pharma companies proclaimed their social consciousness and responsibility by introducing these fixed-dose ARV drugs at lower prices. But in spite of intense pressure from different groups -- positive patient networks, activists and others -- these companies have not reduced prices any further, for a variety of reasons. The government does not help matters and continues to impose a sales tax on these drugs.
When patients are paying for their own treatment, I would agree with the Boston report from Kampala, that the main reason for breaks in treatment is the inability to maintain payments for ARV drugs even at low prices. AIDS and poverty go together. There is definitely a need for subsidizing treatment to make it genuinely affordable.
Dr. Prabhu: ARV fixed-dose drug combinations are available in major metropolitan cities and towns in India. Since only a handful of pharma shops dispense these ARV drugs, it is sometimes difficult to find out where they are or who dispenses them. Patients in the rural areas have to travel long distances to the neighboring big towns or cities, spending huge amounts of money, just to gain access to their drugs. Often the pharma shops run out of stocks especially at the end of the month or stock only certain brands and not others, not offering the entire range to the patients.
Ideally, the only choices that should need to be made with these regimens are whether to start with AZT or d4T, and if it is d4T then to choose a dosage (40 mg or 30 mg) on the basis of body weight (greater or less than 60 kg). Unfortunately, it is not quite that simple in practice.
Lead-In Dosing: Starter Packs Needed
When nevirapine (NVP) is first started, it should be administered at half dose for the first 14 days, i.e. 200 mg once a day instead of twice daily. However, the other drugs in the combination should be administered at full strength. It is clear that this often doesn't happen as it should.
As described by Dr. Martin, below, some patients are still starting on full-dose NVP, risking avoidable NVP reactions. Others have been started on one triple combination tablet a day, so the nucleoside analogues are under-dosed, risking selection for drug-resistant HIV. Hosseinipour reported in Boston that this was done in Malawi, when Triomune first became available in Lilongwe and Blantyre. Studies are now under way to find out whether this led to any avoidable drug resistance. Other patients are prescribed separate drugs for the initial period of treatment. However, as Dr. Prabhu explains, there can be serious problems with this, because the quantities in which the drugs are sold are not matched to how they are meant to be taken.
There is an obvious solution to all of these problems: combining two different fixed dose combinations (with and without NVP) in a blister pack, marketed as a "starter pack." Symbols on a 7-day, 14-dose blister pack could make it clear which tablet/capsule is the morning dose and which is the evening dose. This should be reinforced by clear written instructions in local languages. 7-day packs would also reinforce the point that the drugs must be taken daily (including at weekends) and make them convenient to carry. If patients have to pay for them, they should cost exactly the same as the triple combination drugs so there is no incentive to continue with the starter doses for longer than two weeks.
Dr. Martin: It is our experience (in southern Africa) that with Triomune, patients begin on the higher dose from Day 1. It appears that dose escalation is just too much bother for the physicians to explain and the cost of buying the separate drugs is not something they feel able to inflict on their patients.
Dr. Prabhu: The lead-in or build-up dosing schedule of NVP in combination with d4T/3TC or AZT/3TC is confusing for some patients. NVP is available separately in a container of 60 tablets, which with the lead-in dosage schedule leads to a wastage of about 15 tablets in the initial pill box. Patients do not seem to understand this and continue to consume NVP alone even when the LAMIVIR 30 mg pill box [which also contains 60 tablets] is empty at the end of the month. They feel they must finish both boxes before starting on the next and end up taking NVP alone [which carries a high risk of selecting NVP-resistant HIV], even after any amount of explanation! The patients end up paying hard-earned money for NVP that they cannot and should not use.
Other Packaging Issues
Dr. Prabhu: Certain patients who live far away [from where treatments are available] access their drugs through mail or courier. But on arrival at their home, the tablets are in powder form! These tablets are not packed for long journeys. Pill box covers are very loose and fall off at the earliest opportunity, making it very difficult to identify the drugs the patients are on, especially since doctors who prescribe these drugs do so in secret with no written prescriptions in the patients hands and no means of identification on the tablets themselves. Certain companies package their ARV drugs with a red AIDS logo boldly embossed on the packaging material, which patients find difficult to use, especially when they are traveling in public.
No matter how simple the treatment, it is still vital to spend time making sure that the patient understands how the treatment works.
Dr. Martin: It has been my experience that, provided adequate counseling is given prior to the commencement of ARVs, adherence to the regimens is remarkably good. This is often in the face of difficult work circumstances related to shift-work but the patients have been very innovative in developing strategies to remember their drugs. Clearly simplified dosage forms are preferable (twice-daily). Our experience has shown that the use of "the buddy system" has been the most effective. I think that in our populations where HIV is a rampant epidemic the patients who are able to access antiretrovirals do so with a commitment that will lead to impressive compliance. Peer counselors who themselves have had a turnaround in their disease can be very helpful.
Managing Nevirapine Skin Rash
The main risk associated with NVP, especially in the early stages of treatment, is a skin rash which in its most severe form (Stevens-Johnson syndrome) can be life threatening. Liver toxicity is also of concern and requires prompt action if detected.
If a rash develops, patients need to be advised to return to the clinic to evaluate it. If the rash is mild, then it may be best to try and treat through, so long as patients understand the need to return if the rash gets any worse. Treatment with corticosteroids does not help (in fact it may make it worse). If a rash is severe, or getting worse, then NVP must be stopped. Ideally, the nucleoside analogues should be continued for another week to try and prevent the emergence of virus with resistance mutations to NVP -- so the possibility of using efavirenz (which is vulnerable to the same mutations) is kept open for the future. Liver toxicity is also a serious risk with NVP and monitoring for this is a key responsibility for prescribers.
Dr. Prabhu: NVP skin rash is common, usually mild to moderate. Especially when it affects women and girls, much desperation sets in. The patients may already be suffering from HIV-related pruritic papular dermatitis from which they are seeking relief. Usually with the advent of ARV drugs, their rashes come under control, which can be a good indicator of the success of treatment. But if such a patient develops a NVP-associated skin rash, it becomes exceedingly difficult to distinguish failure of therapy from adverse drug reaction. Serial CD4 counts and HIV RNA viral loads are a luxury few patients can afford. Liver Function Tests might shed light on the subject by showing elevation of transaminases. Finally it boils down to a clinical decision taken on the table, to stop NVP or persist with it and manage the skin rash symptomatically. If the general condition of the patient continues to deteriorate, then it is obvious that ARV drugs are not working and NVP must be stopped and alternatives chosen. A risk versus benefit analysis, and knowledge of any prior ARV use, should guide the decision-making process.
Dr. Martin: Information regarding toxicities involving the liver, skin rashes or Stevens-Johnson Syndrome are lacking: while patients are warned, there is no proper system for reporting adverse events for these unlicensed products. Because these patients have limited financial means laboratory monitoring (liver enzymes) is not carried out in the vast majority of cases.
Downsides to Simplified Treatment?
The idea that HIV treatment can be reduced to one tablet, twice daily, is powerfully attractive to physicians as well as their patients. One risk is that "familiarity breeds contempt."
Dr. Prabhu: Generic pharma companies are as keen as any other to motivate and induce doctors to prescribe their drugs. "Prescriptions, doctor, for our product," "cheap and best," "reminders" are some of their slogans we hear day in and out. With all this pressure from pharma companies, and from patients who are desperate, it is very easy and simple to prescribe, but it needs more than strong will power, at times, to take a balanced decision not to prescribe.
I am no longer surprised to come across prescriptions for these drugs for a short duration of time, sometimes as short as a week's duration, as though we are treating a common cold! Sadly, the concept that, where HIV is concerned, therapy is life long is missing amongst a vast majority of general practitioners [in India]. So if one combination does not work, they just change to the other -- very simple -- with the result that we are soon back to where we started.
Dr. Martin: A source of concern is that the widespread and often sub-optimal use of regimens containing nevirapine will lead to resistance to the nevirapine component and compromise mother-to-child nevirapine-based transmission interruption programs.
How Effective Are These Combinations?
The major reason why NNRTIs such as nevirapine are preferred to protease inhibitors for first-line treatment is that they are more easily tolerated (despite carrying risks, of which patients and providers must be aware). Superior virologic performance has also been reported, almost certainly because these combinations are less dependent than the protease inhibitors indinavir and nelfinavir, in particular, on taking treatment correctly in relation to meals.
One limitation is that NNRTIs are not effective against HIV-2 or HIV-1 group O viruses, so if these are present a protease-inhibitor based combination is likely to be needed.
A randomized trial that compared NVP, efavirenz, and a combination of the two drugs (the 2NN study, funded by nevirapine's maker, Boehringer Ingelheim), was reported at the Boston Retrovirus Conference. It found that NVP and efavirenz gave comparable results in terms of viral suppression. However, there were two deaths (from liver failure) among people treated with nevirapine, which reinforces the need for care in its use.
Following a series of trials which have shown efavirenz to be comparable or superior to protease inhibitors, these reports are important for providers to have confidence that the fixed-dose combinations now on offer can be as effective as more costly treatment options. There is also some data on the equivalence of various NVP formulations, including generic ones. So far, this is reassuring.
Stavudine (d4T) vs. Zidovudine (AZT)
There is a groundswell of medical opinion, in countries where people with HIV usually start medical treatment at CD4 counts above 200, against using d4T as a first-line therapy. The prevalence of neuropathy and a (still-controversial) association between d4T and loss of fat (especially on the face) have relegated the drug to second choice for many. There is clearly a strong case not to prescribe higher doses of d4T than are needed. If a patient weighs less than 60 kg, the 30 mg dose of d4T should be prescribed.
In settings where anemia is widespread (and closely correlates with mortality risk) and patients usually begin treatment at very low CD4 counts, the actual risks are different and it may not be unreasonable for doctors to prefer d4T as their first-line treatment.
The reason why more combinations have been launched based on d4T rather than AZT, is that the higher potency of d4T, by weight, makes it cheaper (per dose) than AZT. At a retail level, this translates to a difference of around $5 per month ($35 vs. $40), which clearly makes treatment more sustainable where patients pay for it.
Lipoatrophy has been seen in Thailand and India, and must be presumed to affect Asian populations as it does Caucasians/Europeans. There is some evidence from both longitudinal and cross-sectional studies that lipoatrophy is more frequent among Caucasians than among people of African descent. So the extent to which it will occur among African populations is still unclear. But for those who suffer from it, the implications will be much the same everywhere.
Dr. Prabhu: AZT is used by a large number of practitioners, though patient tolerance of AZT is low. Complaints of myalgia and headache are common, but what is worrying is development of severe anemia, for which blood transfusions are used enthusiastically with all the attendant risks. Management of ARV drug toxicity is difficult. When HIV is already far advanced and when clinical anemia is obvious, then d4T is the preferred drug. Peripheral neuropathy is painful and slow to respond. Cessation of d4T is sometimes the option chosen, but because of other limited options, dose reduction is attempted to see if it responds.
Dr. Martin: Scant attention is paid [in Southern Africa] to differing dosage forms for Triomune so that a number of patients are overdosed with the 40 mg d4T dosage form and the risk of drug-induced neuropathy is increased; d4T-containing fixed-dose regimens used in the presence of treatment for tuberculosis will lead to increased occurrence of neuropathy.
Best practice in pediatric treatment relies on liquid suspensions, of which a limited range are available, often only in branded versions, at very high prices. For example, in Uganda, no generic suspensions are available, observes Dr. Henry Barigye. Even in India, there is no suspension available for d4T. Yet many babies and young children are anemic and have problems tolerating AZT.
Professor Norman Nyazema, a pharmacologist who has served as a senior technical advisor to the Medicines Control Agency of Zimbabwe, insists there can be no short cuts. Splitting tablets is unacceptable as a basis for licensing a drug for use in pediatric treatment, and if doctors use a drug beyond its license, the manufacturer cannot be held liable for the consequences. Companies that claim they are meeting public health needs by providing low-cost generic formulations must be pressed to provide a full range, including suspensions for pediatric use.
Dr. Prabhu: The lack of choice in pediatric formulations is particularly worrying, since with the increasing number of MTCT interventions that are taking place, more pediatric AIDS cases are being diagnosed. Only AZT, 3TC and NVP suspensions are available. Anemia, which is so common in children, makes it difficult at times to persist with AZT. d4T is chosen, but with lack of availability of pediatric formulations, adult tablets are split to provide for pediatric doses. This is not good practice, but in the absence of alternatives, we are left with no choice!
This article was excerpted from HIV & AIDS Treatment in Practice (HATIP) #2. HATIP is a biweekly email newsletter intended for providers in resource-limited settings. For the full version of this article or to subscribe, visit: www.aidsmap.com.