Durability of Clinical Responses to Anti-HIV Therapies

One time-honored way of acknowledging that a research finding has become mainstream is to see it listed as a clue in the New York Times crossword puzzle. It was thus not unexpected to encounter clue number 42 Down one Tuesday this January: “First drug approved to treat AIDS.”¹ “AZT” fit (as ZDV could have, were it not for competing spaces around it). This started me thinking about how long antiretrovirals have been available to treat HIV infection and about the durability of effects that might be anticipated, in both the resource-rich and resource-poor countries.

One answer comes from the UK Collaborative HIV Cohort, an observational study of the largest HIV clinical centers in the United Kingdom. In this study, 7916 patients who had started antiretroviral therapy with 3 or more drugs were followed up from the time of treatment initiation (between 1996 and 2005) until their last HIV RNA level measurement. ² Only 167 patients (2.1%) developed extensive triple–drug class failure during 27,441 person-years of follow-up.² Virological failure was defined as an HIV RNA level above 400 copies/mL despite more than 4 months of continuous treatment. Extensive treatment failure was defined as the lack of efficacy for all 3 major subclasses of antiretroviral therapy: NRTIs, NNRTIs, and ritonavir-boosted protease inhibitors. The cumulative risk for extensive failure was 3.5% at 5 years and 9.2% at 10 years, and even these low rates have decreased over time.

Clearly, extensive virological failure with the 3 traditional classes of antiretroviral drugs occurs very slowly in routine clinical practice. This was particularly true for those with higher CD4⁺ cell counts at initiation of treatment. The mean CD4⁺ cell count at start of antiretroviral therapy for the study group was 187/µL (range, 90 to 282), but the cumulative risk of drug failure for those starting therapy at CD4⁺ cell counts of 200/µL or higher was 5.5% at 10 years versus 12.1% for those with pretreatment CD4⁺ cell counts below 200/µL.²

Baseline viral load, the initial drug regimen, and sex of the participant (25% were female) were not linked to the rate of drug failure. However, there was a significantly lower hazard ratio for starting with a ritonavir-boosted regimen than for starting with an NNRTI-based regimen, and this hazard ratio increased with longer follow-up (P = .004). Patients who had earlier treatment failure had a 1.5-fold increase in rate of virological failure compared with those never experiencing such failure (P < .001).

Of interest, even among the 167 patients with triple-class resistance, 60.5% subsequently had at least one HIV RNA measurement that was below 50 copies/mL, and the risk of death from the time of recognition of virological failure was only 10.6% at 5 years. This was noted despite the fact that few patients (3%) were treated with regimens containing the fusion inhibitor enfuvirtide and none had received an integrase inhibitor or CCR5 coreceptor antagonist. It appears that substantial antiviral activity of drugs within the 3 traditional antiretroviral drug classes persists even in the setting of extensive triple-class failure.²

These results are very encouraging for the resource-poor world, where access to antiretroviral therapy will most likely be limited to these 3 traditional drug classes for some time.² But it also argues for providing universal access to second- and third-generation drug candidates within those 3 classes, anticipating the end of what some have deemed a “honeymoon period” for antiretroviral therapy in sub-Saharan Africa.³

We also have problems in the United States maintaining the efficacy of antiretroviral therapy among our diverse populations. For example, a group led by epidemiologists from Meharry Medical College in Nashville, Tenn, recently reviewed disparities in black and white mortality rates related to HIV infection in 140 US counties for the period from 1999 to 2002.⁴ Socioeconomic status, race, and pre-HAART era mortality were all significant and independent predictors of post-HAART era mortality.

Changes in age-adjusted mortality among black men and black-to-white mortality rate ratios varied widely among the US counties examined. Percentage change from the pre-HAART era (1990 to 1993) to the post-HAART era (1999 to 2002) ranged from -80% to +325%, with a mean 25% decrease. Of the 140 counties studied, 137 had a mean 139% increase in the black-to-white mortality rate ratio (range, -23% to +724%), and there were no counties with anomalously low ratios.

Although pre-HAART and post-HAART era disparities were not seen consistently for AIDS-defining conditions overall, the percentage of residents who were black, the socioeconomic index, and pre-HAART mortality were all associated with post-HAART mortality among blacks (P < .001). This held true for both sexes and all age groups, although the greatest disparity was seen in those aged 65 and older.⁴ Black women in all age groups had a 13-fold greater risk of dying of HIV than white women.

The reasons for these disparities increasing in the post-HAART era were not investigated. Hypotheses concerned differences in access to information about and the availability of highly active antiretroviral therapy; medical gridlock, ie, the inability by persons with or at risk for HIV infection to access medical service; and differences in epidemic peaks between predominantly white men who have sex with men and black men and women who are more likely to be substance abusers or acquire HIV heterosexually.⁴

Finally, durability of any antiretroviral treatment benefit-precluding the development of an opportunistic infection, malignancy, or other conditions (eg, dementia, metabolic syndromes) linked to HIV infection-will ultimately depend on how well the HIV-infected person’s immune system is reconstituted by his or her drug regimen. This issue has been raised in several previous editorials here,^5-7 and it is very much unsettled. For example, although HIV-positive persons with Kaposi sarcoma usually have CD4⁺ cell counts below 150/µL and high viral loads, San Francisco has recently been host to several cases of unremitting Kaposi sarcoma in persons with undetectable viral loads and CD4⁺ cell counts above 300/µL.⁸ Nine such patients, all receiving highly active antiretroviral treatment (7 regimens contained a protease inhibitor) and without a history of opportunistic infections, were recognized between November 2004 and January 2006.⁸ It was speculated that advancing age-the median age was 51 years (range, 41 to 74)-may have played a role.⁸ If accurate, this is of particular concern given the aging of the HIV population as a whole in the United States.⁹

References:

References

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Shortz W, ed. Crossword.

NY Times

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2.

Phillips AN, Leen C, Wilson A, et al. Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study.

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Mills EJ, Nachega JB. A wake-up call for global access to salvage HIV drug regimens.

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