[e-drug] FDC ARV validated in Cameroon Clinical Trial

[Sean.HEALY@geneva.msf.org]

E-DRUG: FDC ARV validated in Cameroon Clinical Trial
----------------------------------------------------
[Just before the AIDS conference, some good news about FDC ARVs from Cameroon. First the MSF press release, then a comment by Andy Gray (South Africa), finally the Lancet papers. WB]

Dear E-druggers,

Please find below a press release issued by Médecins Sans Frontières
Switzerland, the Agence National de Recherches sur le Sida (France), the
Institut de Recherche pour le Développement (France) and the Ministry of
Health of Cameroon, announcing the successful results of a clinical trial.
The study is published in today's Lancet.

The trial proves the safety and efficacy of the triple fixed dose
combination anti-AIDS drug, Triomune, from the Indian generic manufacturer
Cipla. This is the first ever clinical trial of a generic triple fixed dose
combination.

"Thanks to these findings it is now no longer possible to raise scientific
uncertainty as an objection to the widespread utilization of FDCs in the
developing countries".

The French original is first [suppressed, WB], with the English translation below.

Sean Healy
Information Officer
Campaign for Access to Essential Medicines
Médecins Sans Frontières
Geneva, Switzerland
tel ++41-22-8498 401
fax ++41-22-8498 404
mobile tel ++41-79-239 9271
sean.healy@geneva.msf.org
www.accessmed-msf.org

---
PRESS RELEASE

An advance for HIV/AIDS treatment access in the developing countries

A fixed-dose combination of generic antiretroviral drugs is validated in a clinical trial

Combination  therapy  with  three  generic antiretroviral drugs in a single
tablet has been validated for the first time in an open clinical study in a
developing  country. Follow-up of 60 patients treated in Yaoundé, Cameroon,
has  demonstrated the excellent efficacy and safety of a generic fixed-dose
combination.  The  results  of  this  clinical  trial (ANRS 1274) have been
published  in  The  Lancet   by  a team of researchers from the Institut de
recherche   pour   le  développement  (IRD),  Cameroon  and  Médecins  sans
Frontières (MSF) Switzerland.

Generic  fixed-dose combinations (FDCs) of antiretrovirals are a key factor
in  access to treatment of HIV/AIDS infection in the developing world. FDCs
combine  three antiretroviral drugs in a single tablet and have the twofold
advantage  of being simple to use and substantially cheaper than brand name
drugs.

Lack  of  scientific evidence for the efficacy of FDCs has until now caused
some  international  AIDS  donors  to  refuse  to  fund  the  use  of these
treatments, even though they have recently been prequalified by the WHO.

ANRS  1274  is  the  first  trial  to  provide  scientific evidence for the
efficacy  and  safety  of  an  FDC  in  a  clinical study. The results were
published in the 3 July 2004 issue of The Lancet.

ANRS  trial  1274 was conducted in two hospital centers in Yaoundé (Central
Hospital  and  Military Hospital) within the framework of the Cameroon AIDS
Control  Program  by  a  team  of  researchers  from  the IRD, Cameroon and
MSF/Switzerland.   Of  the  60  HIV-infected  patients  included,  92%  had
full-blown AIDS. The patients were treated with Triomune®, an FDC combining
generic  versions of three antiretroviral drugs from two different classes:
lamivudine,  stavudine and nevirapine. The treatment regimen was one tablet
morning and evening.

Triomune®  is  produced  by  the  Indian pharmaceutical company Cipla. This
generic  combination is now one of the most used in first-line treatment in
the developing world.

"This  trial  demonstrates  in a perfectly rigorous manner that FDCs can be
prescribed in first-line treatment in the developing countries ", explained
Eric  Delaporte  of  the IRD/University of Montpellier, who coordinated the
study   with   Sinata  Koulla-Shiro  of  the  Central  Hospital  and  Eitel
Mpoudi-Ngole  of  the  Military  Hospital  of Yaoundé. The results recorded
after  six  months  of follow-up showed that viral load was undetectable in
80%  of  patients.  Immune  reconstitution  was  significant, with a median
increase  of  83 CD4 lymphocytes/mm3 after six months. Treatment safety was
excellent,  with  a  single  discontinuation of therapy due to adverse drug
reactions.

A  pharmacological  study  showed that plasma antiretroviral concentrations
were  fully  satisfactory  and  equivalent  to  those  observed in patients
treated with brand name drugs.

"This generic fixed-dose combination gives results comparable to those seen
in  the  developed  world  using  triple-drug therapy comprising brand name
drugs", noted Eric Delaporte. "Thanks to these findings it is now no longer
possible  to raise scientific uncertainty as an objection to the widespread
utilization of FDCs in the developing countries ". Nevertheless, "the study
must  be  pursued  to confirm these excellent results over the longer term"
commented  the  Minister of Public Health in Cameroon, Mr. Urbain Olanguena
Awono.

In  Cameroon, where antiretroviral therapy is state-subsidized, the monthly
cost  of Triomune® treatment is 20 US dollars, compared with 35 dollars for
equivalent  triple-drug  therapy  with  brand  name drugs. Cost differences
could vary by as much as 100% in other countries. The demonstrated efficacy
of  generic  FDCs means that from now on more HIV-infected people should be
able to access to treatment.


Source   :  Laurent1  C.,  Kouanfack2  C.,  Koulla-Shiro3  S.,  Nkoué3  N.,
Bourgeois1  A.,  Calmy4  A.,  Lactuock4  B.,  Nzeusseu2  V., Mougnutou3 R.,
Peytavin5   G,  Liégeois1  F.,  Nerrienet6  E.,  Tardy2  M.,  Peeters1  M.,
Andrieux-Meyer4  I.,  Zekeng7/8  L.,  Kazatchkine9  M.,  Mpoudi-Ngolé3  E.,
Delaporte1  E.  for  ANRS  1274  study group, Effectiveness and safety of a
generic  fixed-dose combination of nevirapine, stavudine, and lamivudine in
HIV-1-infected  adults  in  Cameroon : open-label multicentre trial, in The
Lancet 2004, 364, pp.29-34

1   Institut   de  recherche  pour  le  développement  (IRD)/Université  de
Montpellier, France
2 Central Hospital, Yaoundé, Cameroun
3 Military Hospital, Yaoundé, Cameroun
4 Médecins Sans Frontières, Genève, Suisse
5Laboratoire de Toxicologie et de Dosage de Médicaments, Centre Hospitalier
Universitaire Bichat Claude Bernard, Paris, France
6 Centre Pasteur, Yaoundé, Cameroun
7 Laboratoire de Santé et d'Hygiène Mobile, Yaoundé, Cameroun
8 National AIDS Program, Yaoundé, Cameroun
9 Agence nationale de recherches sur le sida, Paris, France

Research contacts:

Eric Delaporte                                       Sinata Koulla Shiro
Eitel Mpoudi-Ngole
IRD/Montpellier                                           Hôpital Central
de Yaoundé                 Hôpital Militaire de Yaoundé
Tél : 04 67 41 62 97                     Tél : +237 223 38 97
Tél : +237 222 62 58
E-mail : eric.delaporte@mpl.ird.fr               E-mail  :
koullasinata@yahoo.fr           E-mail : empoudi@yahoo.uk


Press contacts:

ANRS                                                        IRD
        MSF
Marie-Christine SIMON                     Bénédicte ROBERT          Emma
Amado
Tél : +33 (0)1 53 94 60 30               Tél : + 33  (0) 1 48 03 75 19
Tél : +41 (0) 22 849 84 77
marie-christine.simon@anrs.fr                           presse@paris.ird.fr
emma.amado@geneva.msf.org


---

Hi all

Here's media coverage (from Sunday Times, as "fair use") as well as the abstract of the Lancet article about a clinical trial with Cipla's Triomune (d4T, 3TC, NVP) - the full article is accessible free (as is the whole issue, which focuses on HIV issues). This trial is sure to be criticised - the number of patients was relatively small, the trial was open-label in design, the "undetectable" viral load was high by developed country standards (cf. <50 copies/ml using more modern equipment).

The Lancet also has a very useful commentary on this paper and the whole issue of standard treatment guidelines and the use of generics.

regards
Andy

Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Dept of Experimental and Clinical Pharmacology
* Study Pharmacist
Centre for the AIDS Programme of Research 
in South Africa (CAPRISA)
Nelson R Mandela School of Medicine
University of KwaZulu-Natal
PBag 7 Congella 4013
South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@ukzn.ac.za or andy@gray.za.net
~~~

http://www.suntimes.co.za/zones/sundaytimes/newsst/newsst1088744111.asp 
Good news for Aids drugs
Friday July 02, 2004 06:55 - (SA) 

PARIS - A single dose of three copycat drugs is as effective in combating the Aids virus as the expensive triple cocktail of branded drugs made by pharmaceutical giants, a study says. 

The announcement is being hailed as excellent news for the UN's campaign to distribute antiretroviral drugs in poor countries. 

It is the first clinical scrutiny into whether the much-trumpeted single-tablet generic tritherapy is safe and 
effective. 

Supporters of generics say they are the key to lowering the cost of providing anti-HIV treatment in Africa and other poor, Aids-ravaged locations. 

In addition, by combining three drugs in a single tablet, that offers a big advantage for patients by simplifying an complex daily regime of drug-taking. 

French researchers tested a single dose treatment called Triomune, made by Indian pharmaceutical firm Cipla, among 60 HIV-infected volunteers in the West African state of Cameroon, 92% of whom had full-blown Aids. 

They were given one tablet of Triomune - which combines equivalents of three antiretroviral drugs called lamivudine, stavudine and nevirapine - in the morning and another tablet at night. 

Six months later, HIV levels in 80% of the patients had fallen to below detectable levels, and their once-ravaged immune systems began to be restored, as measured by the count of CD4 white blood cells. 

Levels of drug concentrations in the blood were "fully satisfactory", and equivalent to patients who took brand-name drugs. Patients closely followed the treatment regime. 

"This generic fixed-dose combination gives results comparable to those seen in the developed world using triple drug therapy comprising brand-name drugs," said Eric Delporte, of the France's National Agency for Aids Research (ANRS). 

"Thanks to these findings, it is now no longer possible to raise scientific uncertainty as an objection to the widespread utilisation of (single-dose generics) in the developing countries." 

The research, published in the British medical weekly The Lancet, was showcased at a press conference in Paris on Thursday. 

It will be presented at the July 11-16 International Aids Conference in Bangkok. 

The UN's World Health Organisation (WHO) has set the end of the 2005 as the deadline for giving access to antiretroviral drugs to three million people with HIV. 

The WHO is focussing on sub-Saharan Africa, home to two-thirds of the 40 million people in the world with the human immunodeficiency virus (HIV). 

But of the many obstacles facing this campaign, the biggest is money - and the more cash that can be economised by spending less on drugs, the more lives can be saved. 

The cost of antiretrovirals has fallen sharply in recent years, thanks to goodwill cuts by big pharmaceutical companies and the emergence of copycat equivalents made in Brazil, India and Thailand. 

Big Pharma has fought against generic manufacturers, saying their copying saps the profit motive that drives pharmaceutical innovation, and questioning whether their products meet standards of safety and efficacy. 

The Cameroon study will be extended to assess the long-term effects of using single-dose generics. 

In Cameroon, where antiretroviral therapy is state-subsidised, the monthly cost of Triomune treatment is $20, compared with $35 for equivalent brand-name drugs, ANRS said in a press release. 

However, this price difference could be as wide as $30 per month in other countries. 

Antiretroviral drugs, commonly called the AIDS "cocktail", were introduced in the mid-1990s. 

They stop the virus from replicating after it penetrates an immune cell and hijacks the cellular machinery. 

In many people, they can make HIV a manageable disease, although they are not a cure and there can be toxic side-effects. If the treatment is stopped, the virus rebounds. 

Until now, the beneficiaries of these revolutionary drugs have been in the rich world, simply because of the cost factor. 

AFP

~~~
http://www.thelancet.com/journal/vol364/iss9428/full/llan.364.9428.primary_research.30146.1 

Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial  

Christian Laurent, Charles Kouanfack, Sinata Koulla-Shiro, Nathalie Nkoué, Anke Bourgeois, Alexandra Calmy, Bernadette Lactuock, Viviane Nzeusseu, Rose Mougnutou, Gilles Peytavin, Florian Liégeois, Eric Nerrienet, Michèle Tardy, Martine Peeters, Isabelle Andrieux-Meyer, Léopold Zekeng, Michel Kazatchkine, Eitel Mpoudi-Ngolé, Eric Delaporte, for the ANRS 1274 study group 

Lancet 2004; 364: 29-34

Institut de Recherche pour le Développement and Department of International Health, University of Montpellier (UMR 145), Montpellier, France (C Laurent PhD, A Bourgeois MD, F Liégeois, M Peeters PhD, Prof E Delaporte MD); Central Hospital, Yaoundé, Cameroon (C Kouanfack MD, Prof S Koulla-Shiro MD, V Nzeusseu MD, M Tardy MD); Projet PRESICA/PARVY, Military Hospital, Yaoundé, Cameroon (N Nkoué MD, B Lactuock MD, R Mougnutou MD, F Liégeois, E Mpoudi-Ngolé MD); Médecins Sans Frontières, Geneva, Switzerland (A Calmy MD, B Lactuock, I Andrieux-Meyer MD); Laboratoire de Toxicologie et de Dosage de Médicaments, Centre Hospitalier Universitaire Bichat Claude Bernard, Paris, France (G Peytavin PhD); Centre Pasteur, Yaoundé, Cameroon (E Nerrienet MD); Laboratoire de Santé et d'Hygiène Mobile, Yaoundé, Cameroon (L Zekeng PhD); National AIDS Program, Yaoundé, Cameroon (L Zekeng); and French National Agency for Research on AIDS (ANRS), Paris, France (Prof M Kazatchkine MD)

Correspondence to: Prof Eric Delaporte, Institut de Recherche pour le Développement-UMR 145, 911 avenue Agropolis, BP 64501, 34394 Montpellier cedex 5, France Eric.Delaporte@mpl.ird.fr

Summary 

Background Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine. 

Methods 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis. 

Findings At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per µL (IQR 78-167) and median plasma HIV-1 RNA was 104 736 copies per mL (40 804-243 787). The proportion of patients with undetectable viral load (<400 copies per mL) after 24 weeks of treatment was 80% (95% CI 68-89). Median (IQR) change in viral load was -3·1 log10 copies per mL (-2·5 to -3·6) and in CD4 count 83 cells per µL (40-178). The probability of remaining alive or free of new AIDS-defining events was 0·85 (95% CI 0·73-0·92). Frequency of disease progression was 32·0 (95% CI 16·6-61·5), severe adverse effects 17·8 (7·4-42·7), and genotypic resistance mutations 7·1 (1·8-28·4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. 

Interpretation Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries. 

~~~
http://www.thelancet.com/journal/vol364/iss9428/full/llan.364.9428.analysis_and_interpretation.30169.1 
Generic antiretroviral drugs--will they be the answer to HIV in the developing world?  

Christian Laurent and colleagues, in today's Lancet, report on the efficacy and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon. Highly active antiretroviral therapy (HAART) has led to dramatic reductions in HIV-related morbidity and mortality in the USA and in India.1,2 The use of HAART has led to cost-effective public-health programmes in countries such as Brazil, because there are now fewer episodes of illness and hospital admission.3 The cost of combination HIV-antiretroviral treatment has plummeted in the past 12 months, such that HAART can now be bought for less than US$250 a year from Cipla and other generic companies. Cipla is a drug company in Mumbai, India, that launched the first generic antiretroviral drug, zidovudine, in 1994 (figure). Since then ,Cipla has launched ten different antiretroviral and fixed-dose combinations of antiretroviral drugs as single pills. Falling prices of therapy are enabling physicians in the developing world to offer triple antiretroviral regimens to greater numbers of patients, who desperately need the life-saving drugs. The safety, tolerability, and efficacy of generic antiretroviral regimens for HIV-infected Indians has been shown.4 Also there were earlier reports that generic antiretroviral drugs were successfully used in HIV-infected patients in Africa.5 

The bioequivalency of the generic drugs is equivalent to proprietary drugs.6 Most of the studies and reports used CD4 cell-counts and clinical markers to assess the efficacy of generic antiretroviral treatment.4,5 Laurent and colleagues used HIV-RNA to measure efficacy in African patients and found viral suppression with the generic regimen. These investigators recruited 60 patients in an open-label one-arm 24-week trial. All patients received, twice daily, one tablet of Triomune, which is a fixed-dose combination of stavudine, lamivudine, and nevirapine. The primary endpoint of the study, the proportion of patients with HIV-RNA below 400 copies per mL at 24 weeks was achieved in 80%. The probability of remaining alive or free of new AIDS-defining events was 0·85. Incident rates of disease progression, severe adverse effects, and genotypic resistance-mutations were, respectively, 32·0, 17·8, and 7·1 per 100 person-years. Mean adherence rate was 99%. Median nevirapine, stavudine, and lamivudine concentrations in tablets were 96%, 89%, and 99% of expected values, respectively. 

Similar reductions in viral load with generic drugs made by Cipla were seen in a clinical trial in southern India.7 On the basis of these reports there is no question about safety and efficacy of generic antiretrovirals. Generic antiretrovirals will have a major role in WHO's scaling-up of antiretroviral delivery in their 3-by-5 plan in resource-constrained settings. Because of patents by proprietary companies, newer antiretrovirals may not be manufactured by the generic companies, which might be a major obstacle to patients getting drugs in such settings. 

Adherence to these antiretroviral drugs is crucial to suppress virus levels and prevent resistance.8 In clinical settings, maintaining absolute adherence is a monumental task. In resource-constrained settings, where many patients buy antiretrovirals from a pharmacy because such drugs are not available in government programmes, such patients might stop taking their drugs when they can no longer afford them, which could lead to the emergence of multidrug-resistant HIV. Directly-observed HIV therapy is the key to success.9 

The cost of first-line combination generic antiretrovirals is less than $250 a year. But the cost of the second-line combinations with protease inhibitors is ten times that amount. This large disparity in price will present a great challenge in resource-constrained settings in the scaling-up of antiretroviral delivery. Maintaining the cold chain to store protease inhibitors will also be a challenge in such settings where refrigerators are not available or which suffer power cuts with no backup. 

Immunological and virological monitoring of HIV-infected patients on HAART are critical. The cost of a CD4 cell-count is around $25 a test, and measuring viral load costs $100 a test. The cost of monitoring is higher than the cost of generic antiretrovirals. Mixed results were seen in studies which evaluated usefulness of low-cost total lymphocyte counts in first assessment and monitoring of HIV-infected patients for HAART.10,11 Thus there is an urgent need to evaluate cost-effective simple techniques to measure CD4 cell-count12,13 and HIV-RNA.14,15 

In developing countries, patients who need antiretrovirals often have multiple opportunistic and concomitant infections.2 There are several interactions between drugs for opportunistic infections and antiretrovirals including those leading to varying serum concentrations of drugs.16 Some interactions such as hepatitis, may be fatal, especially those between protease inhibitors and drugs for tuberculosis.17 

Starting, monitoring, and managing the toxicities of antiretroviral drugs is an art and needs tremendous experience and dedication. Physicians need to be trained properly before we scale-up antiretroviral programmes. We need to emphasise that physicians should adhere strictly to standard treatment guidelines to avoid antiretroviral failure and resistance which will be a future public-health challenge in the presence of increasing use of generic antiretroviral drugs. 

N Kumarasamy 

--------------------------------------------------------------------------------
YRG Centre for AIDS Research and Education, VHS, Chennai-600113, India 
Kumarasamy@yrgcare.org 

I am the principal investigator for ACTG/NIH trials for the Chennai site. 

References

1 Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection.  N Engl J Med 1998; 338: 853-60. 
2 Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in Southern India.  Clin Infect Dis  2003; 36: 79-85. 
3 Remien RH, Bastos FI, Berkman A, Terto V Jr, Raxach JC, Parker RG. Universal access to antiretroviral therapy may be the best approach to 'Do no harm' in developing countries: the Brazilian experience.  AIDS 2003; 17: 786-87.
4 Kumarasamy N, Solomon S, Chaguturu S, et al. The safety , tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India.  AIDS 2003; 17: 2267-69.
5 Hosseinipour M, Namarika D, Magomero K, et al. The Malawian antiretroviral program: the first year experience with Triomune. 10th conference on retroviruses and opportunistic infections, Boston, Feb 10-14, 2003: 172 (abstr). 
6 Henry K, Brundage R, Weller D, Akinsete O, Shet A. Comparison of generic zidovudine + lamivudine (Cipla, Duovir) and the GlaxoSmithkline Brand (Combivir) tablets. J Acquir Immune Defic Syndr 2004; 35: 537. 
7 Kumarasamy N, Flanigan TP, Solomon S, et al. Rapid viral load suppression following generic HAART in Southern Indian HIV-infected patients. XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004: ThPeB7137 (abstr). 
8 Chesney M. Adgerence to HAART regimens.  AIDS Patient Care STD 2003 ; 17: 169-77. 
9 Macalino GE, Mitty JA, Bazerman LB, Singh K, McKenzie M, Flanigan T. Modified directly observed therapy for the treatment of HIV-seropositive substance users: lessons learned from a pilot study.  Clin Infect Dis 2004; 38: (suppl 5) S393-97. 
10 Mahajan AP, Hogan JW, Snyder B, et al. Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings.  J Acquir Immune Defic Syndr 2004; 36: 567-75. 
11 Badri M, Wood R. Usefulness of total lymphocyte count in monitoring highly active antiretroviral therapy in resource-limited settings.  AIDS 2003; 17: 541-45. 
12 Balakrishnan P, Mandy Dunne, Kumarasamy N, et al. An inexpensive, simple and manual method of CD4 T-cell quantitation in HIV infected individuals for use in developing countries. J Acquir Immune Defic Syndr (in press). 
13 Josefowicz S, Buchner L, Epling CL, Sinclair E, Bredt B. Simple, low-cost CD4+ T-cell assay: comparison of the Guava Easy CD4 and the BD Biosciences MultiTest assays for the determination of CD4+ T-cell counts in HIV-1-seropositive and -seronegative volunteers. 11th Conference on Retrovirus and Opportunistic Infections, San Francisco, February 8-11, 2004: 96 (abstr). 
14 Malmsten A, Shao XW, Aperia K, et al. HIV-1 viral load determination based on reverse transcriptase activity recovered from human plasma.  J Med Virol  2003; 71: 347-59. 
15 Schupbach J, Tomasik Z, Nadal D, et al. Use of HIV-1 p24 as a sensitive, precise, and inexpensive marker for infection, disease progression and treatment failure.  Int J Antimicrob Agents 2000; 16: 441-45. 
16 Crommentuyn KM, Mulder JW, Sparidans RW, Huitema AD, Schellens JH, Beijnen JH. Drug -drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis.  Clin Infect Dis 2004; 38: e73-75. 
17 Pozniak A. Mycobacterial diseases and HIV.  J HIV Ther 2002; 7: 13-16. 

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