Treatment with generics: tolerability, safety and resistance
Simon Collins, HIV i-Base
As antiretroviral treatment becomes more widely available, through reduced prices and generic combinations, it is important that lessons learned in the first countries to use treatments are not ignored for patients in resource poor countries.
Many access programmes focus on providing treatment, often without the support of viral load or even regular CD4 tests, so it is important to follow the effect of treatment when such studies are presented. This is particularly important as the WHO first-line regimen of generic d4T/3TC/nevirapine based on fixed-dose combinations (FDCs) produced in single formulations is not only the most widely-used but is often the only combination available. This may result in little or no choice for patients accumulating d4T-associated toxicity.
Of note, many studies reported at the Retrovirus meeting included use of this generic combination.
Saple and colleagues from Mumbai reported results from an observational study using generic combinations of efavirenz+3TC-based HAART plus rifampicin-based TB treatment in 60 patients with HIV/TB coinfection. 
The third drug was AZT in 24 patients (regimen cost $1/day) and d4T in 36 patients (regimen cost $1.5/day). Response was assessed in monthly clinical visits and CD4/CD8 results were available every six months. Median increases in CD4 count increase were comparable in the two groups.
Table 1: CD4 increases (cells/mm3)
|d4T (n=36)||AZT (n=24)|
|Median||160 cells/mm3||194 cells/mm3|
|Baseline||(range 93 to 343)||(range 160 to 310)|
|6mo||+ 53 (n =36, p <0.001)||+ 69 (n = 24, p <0.001)|
|12 mo||+ 92 (n = 34, p <0.001)||+ 85 (n = 24, p <0.001)|
|18 mo||+148 (n = 29, p <0.01)||+ 130 (n = 23, p <0.001)|
|24 mo||+163 (n = 32, p <0.001)||+ 197 (n = 22, n <0.001)|
AZT-associated side effects (anaemia) was reported in three patients whereas in the d4T arm, six patients reported peripheral neuropathy. Lipoatrophy in the d4T arm was reported in 12 and 26 patients at week 48 and 72 respectively. This small study concluded that although d4T provided a less costly regimen, the high level of subsequent lipoatrophy limited long-term use.
An observational study from India of more than 1,100 patients using either efavirenz (n=254) or nevirapine (n=857) based combinations reported median CD4 increases from baseline levels of 100 and 115 cells/mm3 to 425 and 377 cells/mm3 respectively at week 24. 
Side effects were sufficient to show the importance of alternative regimens for adequate patient management: peripheral neuropathy in 18% patients using d4T, almost 10% of rash or hepatotoxicity in patients using nevirapine and 20% CNS side effect in patients using efavirenz.
These high levels may be associated with excessive d4T doses (especially with low body weight) and not using the lower 200mg/day induction dose for nevirapine for the initial two weeks. The range of baseline CD4 counts was 2-613 cells/mm3 and 32-741 cells/mm3 in the efavirenz and nevirapine groups respectively, indicating that some people in this study started at much earlier stages of HIV than would be recommended in Europe or the US.
Studies from Thailand, Uganda, Zimbabwe and Nigeria also reported on the more usual reality of patients starting treatment with more advanced HIV including many with baseline CD4 counts <50 cells/mm3. Response rates were generally encouraging and similar to those observed in industrialised countries. [3, 4, 5, 6] Treatment works well – as most optimistic doctors would expect – but higher mortality occurs with when treatment is started with the most advanced HIV disease.
The Nigerian group reported access only to baseline CD4 and hemogram, and no subsequent monitoring available over 18 months follow up in over 70% of patients. Less than 10% of patients had access to regular CD4 or full blood count tests. The study also reported high OI and HIV burden for treating physicians, low experience with antiretroviral treatment and 42% informed consent for patients in the trial.
Patients are at last accessing generic-based combinations. None of these countries provided any significant market for any brand manufacturers and the Western pharmaceutical industry has not collapsed as a result. Future access is threatened by US-determined changes to new trade agreements coming into effect in some countries as early as 2005.
There is a clear need for alternative choices to prevent short-term access to life-saving medications resulting in permanent and debilitating painful neuropathy – as occurred in many patients who continued to use neuropathy-related nucleosides for too long in Western countries. Protease inhibitors are more complex and costly to produce than nucleosides – for example generic nelfinavir is more expensive than the most discounted Roche price, and even this discounted price costs m ore than $800/year. The need for a generic formulation of tenofovir seems compelling.
The importance of use of lower doses of d4T, and increasing patient awareness of early symptoms of neuropathy will also be crucial.
All references are to the Programme and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, 8-11 February 2004, San Francisco.
- Saple D, S Vaidya. Generic AZT vs d4T in HIV/TB co-infection in clinical practice in India: an observational study. 11th CROI 2004, Abstract 583
- Patel AK, Pujari S, Patel KK, et al. Nevirapine- vs efavirenz- based antiretroviral treatment in naïve Indian patients: Comparison of effectiveness in a clinical cohort. 11th CROI 2004, Abstract 584.
- Sungkanuparph S, Vibhagool A, Kiertiburanakul S et al. Initiation of HAART in advanced HIV-infected patients with CD4 <50 Cells/mm3 in a resource-limited setting: efficacy and tolerability. 11th CROI 2004, Abstract 587.
- Bhattacharaya D, Kadzirange G, Zijenah LS et al. Clinical monitoring of cotrimoxazole, Duovir, and Nevimmune (Generic HAART) among men and women with AIDS in Zimbabwe. 11th CROI 2004, Abstract 591.
- Munderi P, C Kityo Mutuluuza C, Reid A. CD4 response to HAART in previously untreated adults with HIV infection in Africa: the DART trial. 11th CROI 2004, Abstract 592.
- Ekong E, Idemyor V, Akinlade O et al. Challenges to antiretroviral drug therapy in resource-limited settings: the Nigerian experience. 11th CROI 2004, Abstract 596.