aHôpital FOCH, Suresnes, France
bFrance Expertise Internationale, Paris, France
cPharmaco-Toxicology Department, Hôpital Bichat, Paris, France.
Correspondence to Dr David Zucman Hôpital Foch, Service de médecine interne 92150 Suresnes France. E-mail: email@example.com
Received 23 September, 2013
Revised 28 November, 2013
Accepted 28 November, 2013
Although second-line generic antiretroviral drugs are of great value in developing countries, there are concerns regarding their quality. We studied a generic Lopinavir/ritonavir (200/50 mg; Arga-L, India) marketed in the Republic of Congo but not prequalified by WHO. Despite adequate quantitative and qualitative drug content, Arga-L had a bio-availablility of 10% compared with Kaletra. To avoid selection of drug-resistant HIV, rigorous pharmacological monitoring of generic drugs not prequalified by WHO must be a priority.
According to UNAIDS , 34 million people worldwide were infected by the HIV at the end of 2011 and, of these, 69% were living in sub-Saharan Africa. Generic products have greatly reduced the costs of antiretroviral drugs (ARVs), and have improved access to treatment for HIV-infected patients in developing countries. Clinical trials with first-line generic drugs have shown excellent results in sub-Saharan Africa . The majority of ARVs marketed in resource-limited countries are generics and their increased availability has transformed AIDS therapy and generated broad-based gains to health. Since 1995, antiretroviral therapy has saved 14 million life-years in low-income and middle-income countries, including 9 million life-years in sub-Saharan Africa .
However, an inevitable consequence of the widespread availability of ARVs is treatment failure caused by the development of new strains of drug-resistant viruses . A subset of individuals who acquire drug-resistant HIV will transmit their drug-resistant virus to others. This scenario has a potential impact on mortality and treatment outcomes . Therefore, there is now a need to scale-up access to second-line generic treatments in these countries.
Lopinavir/ritonavir (LPV/r) is the cornerstone of second-line ARVs in the developing world [5,6]. A growing number of generic LPV/r drugs are now available, but their quality and safety are still of concern. There are only very limited published data concerning the pharmacokinetic and clinical properties of generic LPV/r drugs. A generic LPV/r product produced by the Government Pharmaceutical Organization of Thailand was found to have adequate plasma drug levels in a short-term study  and good tolerability, efficacy, and drug levels in a 48-week study in Thai HIV-infected patients . However, several generic LPV/r tablets tested in a dog model showed very variable bioavailability depending on the drug tested, with some compounds having a bioavailability as low as 1% compared with the LPV/r brand Kaletra .
In order to guarantee quality and facilitate government purchasing choices, the WHO has drawn up a prequalification list for generic ARVs . However, this list does not indicate the reasons for exclusion, particularly quality defects, or if there are no or scanty comparative bioequivalence studies with the equivalent brand-name product. Furthermore, the increasing extent of market competition between generic manufacturers necessitates dynamic on-going surveillance to monitor the quality and production of generic medications, as well as combined in vitro and in vivo studies of patients.
In 2012, a generic LPV/r manufactured in India was introduced into the Republic of Congo, and our group had an opportunity to study this drug. We report here on the case of a French subject of sub-Saharan origin who visited Brazzaville (Republic of Congo) and received postexposure prophylaxis following unprotected sexual intercourse. After admission to the main HIV-treatment centre (CTA Brazzaville), he received generic ARVs at the usual doses, containing zidovudine/lamivudine (AZT/3TC) and LPV/r (200/50 mg; Arga-L, McNeil & Argus, India).
When he returned to France 2 days later, the patient presented to our hospital for a follow-up. The physician, intrigued by the unusual appearance of the LPV/r tablets (small, flat, circular and white), measured minimal drug levels (C12 h) in the patient's plasma. Concentrations of LPV and ritonavir (RTV) were undetectable, suggesting that the patient was noncompliant, that the generic LPV/r was defective, or there had been poor intestinal absorption. After checking the WHO prequalification list, it appeared that Arga-L was not prequalified. Therefore, we performed qualitative and quantitative pharmacological analyses to evaluate the content, quality, and oral bioavailability of the compounds within the Arga-L tablets and then compared the results with the reference pharmaceutical formulation, Kaletra (Abbvie, France).
Coupled liquid chromatography-tandem mass spectrometry analyses of the tablets were performed after crushing and dissolution in an appropriate solvent. Qualitative analysis of the Arga-L tablet identified the correct drug substances: LPV and RTV. Moreover, quantitative analysis indicated adequate unit masses of 215 mg of LPV and 50.8 mg of RPV, comparable to those of Kaletra.
To evaluate oral bioavailability of the drug substances, C12 h of LPV and RPV were measured in four healthy volunteers after a single oral dose of the generic LPV/r Arga-L (400/100 mg) taken during an evening meal. A 1-week wash-out later, the same subjects were given the brand-name LPV/r product Kaletra (single dose 400/100 mg) and the analysis was repeated.
As shown in Table 1, LPV and RTV C12 h after Arga-L intake were considerably lower than those observed for the brand-name drug Kaletra, revealing quality issues of the generic drug.
Thus, despite adequate qualitative and quantitative composition of the generic Arga-L, when C12 h was measured in the five subjects (one case of postexposure prophylaxis and four controls) there was a very low oral bioavailability of generic lopinavir and ritonavir (<10%) compared with the brand-name drug. These results also strongly suggest that bioequivalence studies were not validated between these two pharmaceutical drugs.
Because of the low, albeit not null, bioavailability of lopinavir and ritonavir compounds in the generic Arga-L, its usage in HIV-infected patients may increase the risk of virological failure through the emergence of resistance mutations. Purchasing generic ARVs in accordance with the WHO prequalification list  or the Food and Drug Administration list  is therefore crucial in African countries because of the risk of disastrous consequences in terms of public health. The lack of regulations formulated by Northern countries regarding this issue clearly shows the need for thorough evaluation of nonprequalified generics.
Our results emphasize the crucial requirement of testing for human bioequivalence of generic products that contain LPV/r to guarantee their efficacy before these products are made available to patients. National authorities and funding agencies should require that such quality-assurance processes are conducted and approved.
D.Z. took care of the index case. D.Z. and G.P. designed the study. D.Z., S.C., J.G. and M.V. were healthy volunteers for the pharmacological study. G.P. and M.C. performed the pharmacological analysis. A.G. and S.D. provided useful information concerning access to antiretroviral drugs in Republic of Congo. All authors wrote the article.
Conflicts of interest
There are no conflicts of interest.
No funding was received for this article.
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