Recent Highlights in Clinical AIDS Research

Last month I reviewed key findings in HIV that were published within a 2-month interval near the end of 2007. I have extended that review here, reporting highlights of research announced in the last few weeks of 2007.

RACIAL DIFFERENCES IN VIROLOGICAL FAILURE
Race may be an independent predictor of virological response to at least certain types of antiretroviral therapy. It has long been recognized that virological failure rates are intimately related to medication adherence, although the magnitude of that association may vary by antiretroviral drug class as well as by the type of measure used to assess adherence.¹ A recent analysis of 715 patients-299 white, 260 non-Hispanic black, and 156 Hispanic of any race-randomized to a regimen of zidovudine, lamivudine, and efavirenz or to a regimen of zidovudine, lamivudine, abacavir, and efavirenz as part of AIDS Clinical Trials Group (ACTG) protocol A5095 found that blacks had higher rates of virological failure than whites.1 Such failure, defined as HIV RNA levels of 200 copies/mL or higher after 16 weeks of treatment, was linked to differences in both adherence at week 12 (P = .02) and self-assessed quality of life (QOL) (P < .001).

This is the second large study to document black race as an independent predictor of virological failure.^1,2 Using the metric of a missed dose within 4 days of a clinic visit as a determinant of medication adherence, there were significantly higher proportions of nonadherence in blacks than in whites at week 4 (20% vs 11%, respectively) and week 12 (22% vs 12%).1 Overall, mean QOL scores increased from 73.0 (±19.5) at baseline to 78.3 (±16.9) at week 12 and 83.3 (±14.4) at 2 years, independent of race and gender, but participants with recent QOL scores either below 75 or between 75 and 89 had more than twice the risk of virological failure as participants with higher scores.¹

Racial and ethnic differences in responses to efavirenz-based treatment are critical to understand because efavirenz-based regimens represent major first-line therapies worldwide. Lessons from investigations such as those cited above could also inform treatment guidelines for other regimens, including protease inhibitor (PI)-boosted and NNRTI-based therapies. But apart from behavioral effects and adverse events that might drive medication adherence and thus virological response, physiological differences may also play a role.

For example, among patients in an ACTG A5095 substudy, there was a strong association between a polymorphism in the hepatic enzyme CYP2B6, which is responsible for efavirenz metabolism and is more common in blacks than whites, and higher plasma levels of efavirenz as well as earlier CNS symptoms.³ This enzyme mutation is particularly prevalent in sub-Saharan Africa: 49% of HIV-positive blacks being treated with an efavirenz-based regimen in Zimbabwe had the mutant CYP2B6 allele, together with high efavirenz drug levels.⁴ This may complicate patient adherence to treatment unless dose optimization informed by measures of plasma drug levels is sought. The issue deserves further study, including determination of the extent of CYP2B6 polymorphism in Asian populations.

LIPODYSTROPHY AND MANIPULATION OF GROWTH HORMONE
In about 40% of HIV-positive adults, an adipose redistribution syndrome develops, characterized by excessive truncal fat, including visceral (deep abdominal) adipose tissue.⁵ This may or may not be accompanied by loss of subcutaneous adipose tissue from the abdomen, face, and extremities. Persons with this redistribution syndrome, as well as those with HIV-related lipoatrophy in the absence of excess visceral adipose tissue, often manifest glucose and lipid abnormalities. They are also at greater risk for cardiovascular disease than are HIV-positive persons without fat maldistribution.⁵

Development and progression of these metabolic syndromes typically occurs within 3 years of antiretroviral treatment initiation.⁶ They may be more common in those taking PI-based regimens.⁷ No drugs are currently FDA-approved for the treatment of adipose redistribution. The use of insulin sensitizers or lipid-lowering agents, physical exercise, and diet modification are of limited benefit.⁸ Switching certain drugs in antiretroviral regimens can decrease the amount of visceral adipose tissue and mitigate metabolic syndromes,⁹ but these changes are slow and the option to alter antiretroviral drug regimens is not available to many. Recombinant human growth hormone (Serostim, Serono) at a dosage of 4 mg daily for 12 weeks has been shown to significantly reduce visceral adipose tissue and trunk fat and improve lipid metabolism, perception of body image (eg, “belly profile” and “belly image distress” concerns), and QOL.⁵ A maintenance dosage of 2 mg given on alternate days for 36 weeks has served to sustain visceral adipose tissue and trunk fat losses and did not result in loss of subcutaneous fat.⁵ But this is an expensive approach for relatively modest benefit.

To evaluate more physiological methods of growth hormone replacement, the use of several analogs of growth hormone-releasing hormone (GHRH) has been tried. In the latest reported study, 2 mg of tesamorelin, a GHRH analog modified to prevent protein cleavage in vivo, or placebo was administered subcutaneously once daily for 26 weeks to 412 HIV-positive persons with excessive visceral adipose tissue.¹⁰ This was followed by a second 26-week phase in which 77% of the patients underwent a second randomization to either tesamorelin or placebo.

The use of this GHRH analog resulted in a 15.2% decrease in visceral adipose tissue, compared with a 5.0% increase among participants who received placebo (P < .001), with a parallel improvement in body image and lipid profiles among the 326 participants who completed the first 26-week cycle.¹⁰ Insulinlike growth factor (IGF-I) levels, the primary factor mediating local effects of growth hormone, increased by 81% in the tesamorelin group.¹⁰

There were no drug-related serious adverse events, although IgG anti-tesamorelin antibodies developed in about half the participants exposed to tesamorelin.¹⁰ But there are 2 major concerns regarding the assessment of tesamorelin use in HIV disease:

- Will the changes produced by a GHRH analog translate into decreased cardiovascular morbidity?

- Will overstimulation of the pituitary gland or CNS lead to an increased risk of pituitary neoplasia, neurobehavioral dysfunction, or other adverse effects of overstimulation?¹¹

Cost is another issue. As one editorialist has suggested, “. . . without answers to these questions, the treatment of HIV lipodystrophy remains unresolved.”¹¹

MALE CIRCUMCISION
A year ago, in an editorial highlighting a “year in AIDS,” my very first bullet point was male circumcision.¹² Three randomized controlled interventions conducted in Africa among general populations of uncircumcised men found that medical circumcision afforded a protection rate against acquisition of HIV via penile-vaginal intercourse ranging from 48% to 60% over a mean follow-up of about 18 months.¹² Since publication of these results, health professionals worldwide have considered the utility of this procedure as an HIV prevention strategy, one which promises effectiveness equivalent to that of an antiviral vaccine.

The applicability of those studies among male heterosexuals to men who have sex with men (MSM) is unclear. A recent respondent-driven sampling of 1154 black and 1091 Latino MSM from 3 major US cities found that circumcision status was not associated with prevalent HIV infection, nor was it associated with a reduced likelihood of HIV infection among men who had engaged in unprotected insertive but not unprotected receptive anal intercourse.¹³ Given these data, and the possibility of behavioral disinhibition effects predicated on an assumption of efficacy, the utility of male circumcision as an HIV prevention measure among the MSM population remains to be demonstrated. Indeed, although circumcision is the most common surgical procedure in males, predominantly because of religious and cultural reasons, the only absolute medical indications for the procedure are balanitis xerotica obliterans and a scarred foreskin.¹⁴

Complications following circumcision occur in 1% to 7% of cases. Some pediatric groups list the prevention of penile and cervical cancer as a relative indication for circumcision, but the data for this are unclear.¹⁴ In terms of HIV prevention in populations apart from those studied in Africa, circumcision in general, as well as the timing of the operation, should be considered a relative indication at best.

HIV DRUG RESISTANCE
Nine HIV-1 PIs are currently FDA-approved. These agents inhibit the ability of viral protease to process the HIV-1 polypeptides Gag and Gag-Pol during the final stages of virion maturation.¹⁵ All are highly potent clinically, but the emergence and rising frequency of multidrug-resistant viruses has led to a high incidence of cross-resistance among PIs, limiting their sequential use.¹⁵ However, the latest PI to be approved, darunavir (TMC114; Prezista), has an exceptionally high binding affinity for wild-type protease. PI mutations leading to a 3-log–fold decrease in binding affinity for the drug had little impact on darunavir’s antiviral activity.¹⁵

Most mutations within the protease gene that suppress inhibitor activity do so by altering binding affinity of the enzyme’s normal substrates, either by decreasing protease-drug association rates or increasing protease-drug dissociation rates.¹⁵ Most PI mutations that occur clinically involve the latter process yet have little impact on darunavir’s activity. This was first shown clinically in the phase 2b POWER 1 study.¹⁶ Among patients with HIV RNA levels greater than 1000 copies/mL and 1 or more primary PI mutations (58% had 3 or more such mutations per the new International AIDS Society–USA guidelines¹⁷), ritonavir-boosted darunavir led to higher virological response rates and CD4 count increases than treatments with investigator-selected control PIs.¹⁶

Recent reviews have documented significant improvements in survival among patients starting antiretroviral treatment with newer PIs compared with first-generation PIs or the NNRTI nevirapine.¹⁸ Agents such as darunavir, along with additional PIs in early phases of clinical testing and 2 new classes of anti-HIV drugs-integrase inhibitors and CCR5 coreceptor inhibitors-should also have a major impact on the treatment of drug-resistant HIV disease.

References:

References1. Schackman BR, Ribaudo HJ, Krambrink A, et al. Racial differences in virologic failure associated with adherence and quality of life on efavirenz-containing regimens for initial HIV therapy. Results of ACTG A5095. J Acquir Immune Defic Syndr. 2007;46:547-554.
2. Hartzell JD, Spooner K, Howard R, et al. Race and mental health diagnosis are risk factors for highly active antiretroviral therapy failure in a military cohort despite equal access to care. J Acquir Immune Defic Syndr. 2007;44:411-416.
3. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult Clinical Trials Group study. AIDS. 2004;18:2391-2400.
4. Nyakutira C, Röshammar D, Chigutsa E, et al. High prevalence of the CYP2B6 516G→T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol. 2007 Dec 5 [Epub ahead of print].
5. Grunfeld C, Thompson M, Brown SJ, et al. Recombinant human growth hormone to treat HIV-associated adipose redistribution syndrome: 12-week induction and 24-week maintenance therapy. J Acquir Immune Defic Syndr. 2007;45:286-297.
6. Wand H, Calmy A, Carey DL, et al. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS. 2007;21:2445-2453.
7. Homsanit M, Nelson KE, Sonjai A, et al. Body shape and metabolic abnormalities in Thai HIV-infected patients. AIDS Res Hum Retroviruses. 2007;23:1314-1321.
8. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62.
9. Haubrich R, Riddler S, DiRenzo G, et al. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 38.
10. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357:2359-2370.
11. Blackman MR. Manipulation of the growth hormone axis in patients with HIV infection. N Engl J Med. 2007;357:2397-2399.
12. Laurence J. Highlights of a year in AIDS. AIDS Reader. 2007;17:107-109, 120.
13. Millett GA, Ding H, Lauby J, et al. Circumcision status and HIV infection among black and Latino men who have sex with men in 3 US cities. J Acquir Immune Defic Syndr. 2007;46:643-650.
14. Malone P, Steinbrecher H. Medical aspects of male circumcision. BMJ. 2007;335:1206-1209.
15. Dierynck I, De Wit M, Gustin E, et al. Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J Virol. 2007;81:13845-13851.
16. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS. 2007;21:395-402.
17. Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006;296:827-843.
18. Crane HM, Van Rompaey SE, Kitahata MM. Initiating highly active antiretroviral therapy with newer protease inhibitors is associated with better survival compared to first-generation protease inhibitors or nevirapine. AIDS Patient Care STDS. 2007;12:920-929.