Initiating Antiretrovirals in India certain critical issues

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Initiating Antiretrovirals in a Resource-Constrained Setting: Does

One Size Fit All?

From Medscape General Medicine™ eJIAS: eJournal of the International

AIDS Society. Posted 08/08/2005

Ajay Wanchu, MD, DM

Introduction.

The World Health Organization (WHO) aims to provide antiretroviral

therapy (ART) to at least 3 million patients in resource-limited

settings by the end of 2005, an initiative referred to as " 3 by 5. "

The program uses a CD4+ cell count of 200 cells/microliter (mcL) for

initiating treatment as a cutoff in asymptomatic individuals.[1]

Some issues need to be addressed when applying the program in

resource-constrained countries such as India.

Limitations of WHO-Recommended Regimen Applied in India

Reduction in viral load might reduce transmission of HIV.[2] The

combination of drugs primarily used in the WHO-approved regimen are

nevirapine, lamivudine, and stavudine. This is the cheapest generic

formulation in India that has the advantage of combining all 3 drugs

in 1 pill. The cost of this combination is less than $1 per day.

However, in the free treatment program, the number of patients who

would require these medications worldwide will increase rapidly.

Worldwide, 16,000 individuals get infected daily and each would,

sooner, rather than later, require ART. In India, all of the 5

million-plus patients would be candidates for treatment. Do we have

resources to provide medication even at less than $1 per day?

It is notable that although nevirapine-based regimens have been

shown to do as well as other regimens, the drug has never been

the " most preferred " in most international guidelines.[3] The other

issue is one of resistance with nevirapine, as a single amino acid

substitution in the reverse transcriptase gene can result in

resistance to the whole nonnucleoside reverse transcriptase

inhibitor (NNRTI) class of drugs.[4] Once resistance develops the

transmissibility of the virus decreases, but what are the options

for those who develop resistance? In most instances, anyone who

develops resistance today has few options because alternative

regimens are far too costly. Because no baseline nevirapine

resistance rates in treatment-naive patients are available in India,

there is no knowledge about the percentage of individuals who are

unlikely to respond to the ART offered by the 3 by 5 initiative in

the first instance.

Can Treatment Be Deferred?

Are we treating patients when they can do without ART? Can we defer

treatment in asymptomatic patients? Perhaps we can. Western cut offs

to initiate ART may not be appropriate, as some studies have shown

lower CD4+ cell counts in apparently healthy Indians. In one study,

the range of CD4+ cell counts in healthy Indians started from just

over 300 cells/mcL.[5] Another study carried out in 200 healthy

Indians showed that CD4+ cell counts ranged between 304 and 1864

cells/mcL.[6] A modest decline early in the course of disease might

qualify the patient for initiation of ART. Can we wait longer

until " chronic immune failure " develops, as early initiation means

that patients lose their only therapeutic option much faster?

Another issue relates to pitfalls in using guidelines where CD4+

cell counts decide treatment. Does one size fit all? Thus, while

cytomegalovirus (CMV) infection develops most often with CD4+ cell

counts < 50 cells/mcL, does everyone with a CD4+ cell count < 50

cells/mcL develop CMV disease? Surely no. Do we, then, treat

everyone on the basis of a CD4+ cell count that tells us that an

individual with CD4+ cell count < 200 cells/mcL is at heightened

risk for opportunistic infections (OIs), even though a fraction do

not develop OIs?

The crucial issue is: Are we treating patients in resource-

constrained settings far too early and running the risk of

exhausting their therapeutic options much earlier rather than

starting therapy later and providing a longer survival on the same

regimen and resources? It could be argued that deferring therapy for

too long would compromise the patient's ability to recover pathogen-

specific immune responses. However, is a patient with advanced

immunosuppression with a CD4+ cell count of 175 cells/mcL, but free

of OI, an ideal candidate to initiate ART when all he has by way of

therapeutic options is the first regimen that the WHO provides?

Perhaps no. Therapeutic options in the underprivileged begin and end

with the first and only regimen. In addition, early treatment would

result in earlier resistance to nevirapine. Can we use the available

agents more judiciously to prolong survival? If not everyone with a

CD4+ cell count < 200 cells/mcL develops OI, should everyone then be

made to take ART when we do not know the risk of developing OIs in a

given individual?

Current Status and Short-term Needs

The recent WHO report that provides an update on the 3 by 5 program

should provide food for thought to policy makers regarding the

financial implications of providing treatment under the program:

The estimate of approximately 1 million people now on treatment

falls short of the milestone of 1.6 million set in the WHO/UNAIDS " 3

by 5 " strategy for June 2005. Current data and trends indicate that

providing ART to 3 million people by the end of 2005 will be

unlikely. However, there is reason to be hopeful that growth rates

will continue to increase in the remainder of 2005 and beyond.

Although less than what is needed, an estimated US$27 billion are

available or have been pledged for HIV/AIDS globally from all

sources for the three-year period 2005-2007. UNAIDS estimates that

at least an additional US$18 billion above what is currently pledged

is needed for global HIV/AIDS efforts over the next three years,

including treatment, care and prevention. Donors should continue to

increase their financial commitments, and work with countries to

develop long-term funding arrangements that assure sustained and

predictable support.[7]

Like several countries, including India, the WHO is also resource-

constrained. Under these circumstances, will second-line agents be a

realistic option, even though each one of the 5 million-plus

patients in India (plus those in the rest of the developing world)

would become candidates for these, sooner or later (sooner, rather

than later, if we initiate treatment early)?

Summary and Conclusions

We must look for alternative mechanisms that can identify

individuals at greater risk of developing an OI. At a bare minimum,

we must reconsider the 200 cells/mcL CD4+ cell count cut off for

initiating ART among those who are asymptomatic.

References

1. World Health Organization. The 3 by 5 initiative. Available

at: http://www.who.int/3by5/en/ Accessed July 29, 2005.

2. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and

heterosexual transmission of human immunodeficiency virus type 1. N

Engl J Med. 2000;342:921-929. Abstract

3. Ivers LC, Kendrick D, Doucette K. Efficacy of antiretroviral

therapy programs in resource-poor settings: a meta-analysis of the

published literature efficacy of antiretroviral therapy programs in

resource-poor settings: a meta-analysis of the published literature.

Clin Infect Dis. 2005;41:217-224. Abstract

4. Calvez V, Delaugerre C, Rohban R, et al. Resistance profile

and cross-resistance of HIV-1 among 102 patients failing a non-

nucleoside reverse transcriptase-inhibitor based regimen. Antiviral

Ther. 2000;5(suppl 3):97-103.

5. Nag VL, Agarwal P, Venkatesh V, Rastogi P, Tandon R, Agrawal

SK. A pilot study on observations on CD4 & CD8 counts in healthy HIV

seronegative individuals. Indian J Med Res. 2002;116:45-49. Abstract

6. Amatya R, Vajpayee M, Kaushik S, Kanswal S, Pandey RM, Seth

P. Lymphocyte immunophenotype reference ranges in healthy Indian

adults: implications for management of HIV/AIDS in India. Clin

Immunol. 2004;112:290-295. Abstract

7. World Health Organization. Progress on Global Access to HIV

Antiretroviral Therapy: An update on 3 by 5. June 2005. Available

at: http://www.who.int/3by5/fullreportJune2005.pdf Accessed July 29,

2005.

_________________________

Ajay Wanchu, MD, DM, Department of Internal Medicine, Postgraduate

Institute of Medical Education and Research, Chandigarh, India.

Email: awanchu@...

Disclosure: Ajay Wanchu, MD, DM, has disclosed no relevant financial

relationships.

Medscape General Medicine. 2005;7(3) ©2005 Medscape

(http://www.medscape.com/viewarticle/508879).