Time for Tenofovir in First-line HIV Therapy in Resource-Limited Settings?

Time for Tenofovir in First-line Treatment in Resource-Limited Settings?

Most initial highly active antiretroviral therapy (HAART) regimens in resource-limited settings still include stavudine (d4T) or -- to a lesser extent -- zidovudine (ZDV), largely due to cost and availability considerations.^[1]

However, the toxicity profile of these nucleoside reverse transcriptase inhibitors (NRTIs) -- d4T, in particular -- makes them less than ideal choices.

d4T is associated with high rates of toxicity and side effects in resource-limited settings; this toxicity not only adversely affects patient quality of life, but may lead to treatment changes, discontinuation of therapy, and even death.^{[2,3,4,5,6,7,8,9]} The toxicities observed most frequently with d4T in resource-limited settings are similar to those seen in well-resourced settings, and include peripheral neuropathy,^[3,4] lactic acidosis,^[5,6,7] and lipodystrophy.^[8,9] ZDV is also associated with a significant degree of treatment-limiting toxicity (mainly anemia and neutropenia) when used in resource-limited settings, particularly in patients who are already at risk for cytopenias as a consequence of advanced AIDS.^[10,11] Many resource-limited settings wherein HAART is administered are not able to routinely monitor laboratory indicators of toxicity, such as transaminases, electrolytes, hematology, or lactate tests.

One logical question, therefore, is whether tenofovir (TDF) should replace d4T or ZDV as a component of first-line regimens in resource-limited settings, despite its higher cost and different toxicity profile. TDF (Viread^®) was the first nucleotide analog for the treatment of HIV, approved in 2001 for treatment of HIV-1 infection in combination with other antiretroviral medications. The World Health Organization included TDF as a preferred first-line NRTI in its 2006 antiretroviral therapy guidelines. There are advantages and disadvantages of using TDF in first-line regimens.

Advantages of TDF in First-line Treatment

The advantages of TDF in first-line treatment include the following:

Lower rate of treatment-limiting toxicity; the primary toxicity of TDF is renal (see below);
TDF is very well tolerated by patients;
Once-daily dosing;
Generally preserves susceptibility to ZDV in second-line treatment;
Treats hepatitis B in patients with HIV-hepatitis B coinfection; and
May actually be cost-effective in resource-limited settings.^[12,13]

Disadvantages of TDF in First-line Treatment

The disadvantages of TDF in first-line treatment include the following:

TDF is still more expensive than generic d4T or ZDV. However, generic versions of TDF have received tentative US Food and Drug Administration (FDA) approval, and the price of TDF in resource-limited settings has been decreasing
Nephrotoxicity. Most studies have demonstrated an overall slight (and generally clinically insignificant) decline in creatinine clearance (CrCl) among patients on TDF,^[14,15,16] with less than 1% of patients experiencing significant declines in renal function. Patients with normal renal function at baseline, who are not taking concomitant nephrotoxins, are at low risk for clinically important renal toxicity
- Clinically significant nephrotoxicity may occur more frequently than is reflected by carefully selected clinical trial populations, and perhaps more frequently in resource-limited settings.^[17] Decreases in bone mineral density have also been observed in association with TDF use
- Patients in Africa seem to have lower CrCl at the time of treatment initiation than patients elsewhere,^[18,19] although this may be related to the way CrCl is estimated in patients with very low body weight^[20]
- Optimal approach to estimating CrCl in patients in resource-limited settings remains unknown,^[19] even when chemistry testing is available,^[20] and many treatment sites do not currently have access to creatinine monitoring
In vitro studies have suggested that the K65R mutation may emerge more rapidly with subtype C virus than with other subtypes^[21] in patients on TDF treatment. Subtype C predominates in some of the hardest-hit resource-limited settings, such as sub-Saharan Africa and India.

Some national treatment programs in resource-limited settings, including those in Zambia and Botswana, have adopted the use of TDF in first-line regimens. In a large program in Zambia, early data suggested that TDF is associated with lower rates of treatment switches and is better tolerated than d4T or ZDV.^[22]

Drs. Benjamin Chi and Jeff Stringer, co-investigators of the Zambian study, reported (email correspondence, September 2009):

In cohort analysis of 10,485 patients in Lusaka, Zambia, we found that adults on first-line TDF-based ART had similar clinical and programmatic outcomes compared with those on alternative regimens. The only difference was in regimen tolerability. Patients on ZDV- and d4T-based ART were twice as likely to undergo single-drug substitution compared with those starting on TDF, with the highest risks observed in the 90 days after initiation. Given the high risk of early mortality and the need to minimize toxicity in these severely ill patients, we believe that TDF-based ART regimens should be considered as first-line treatment in resource-limited settings. These benefits should be weighed against the higher cost of the drug and the need for more intensive renal monitoring at the site level.

Editor's Note

If you have comments or questions on this topic, or would like to share your experiences related to the use of TDF in first-line treatment of HIV in resource-limited settings, please join our discussion .

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