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Complications of HIV infection. A summary form the IDSA/ICAAC conference in Washington DC.
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Pablo Tebas
University of Pennsylvania
Introduction
The complications of antiretroviral therapy continue to be one of the main concerns of patients living with HIV. The development of new drugs and new antiretroviral combinations with better toxicity profiles have made the frequency of the traditional metabolic complications associated with antiretroviral treatment somewhat less frequent in our clinic population. However, we continue to learn that HIV infection itself is a significant contributor of the so called "non-AIDS related morbidity" that our patients are prone to suffer. A couple of years ago, the SMART study showed that unabated viral replication is associated with a milieu of complications including cardiovascular events, liver and renal problems and cancers. Data presented in this meeting suggest that the contribution of HIV itself to these co-morbidities, traditionally not associated with HIV, may be significant even in individuals with high CD4 counts. Studies are showing again and again that ongoing viral replication can be problematic even with high CD4 cells counts. The availability of less toxic regimens may tip the balance towards treating patients earlier than our current recommendations. Data from the NA-ACCORD observational cohort suggests that patients with a relatively high CD4 cell count (over 350 cells/mm3) benefit from antiretroviral therapy even if they are not IVDU or HCV co-infected. The relative risk of death is 1.7 times higher in the patients not receiving antiretroviral therapy (95% CI 1.4-2.1) (H-896b) 14. This was not the only study showing similar findings: a study from Spain showed that patients with high CD4 counts and HCV co infection have less inflammation and fibrosis in their livers if they are receiving antiretroviral therapy (H-2319)13. As the HIV infected population ages, this type of non-AIDS related problems become more relevant in the clinical management of our patient population. According to the CDC, older adults represent up to 15% of the AIDS caseload, an increase of about 5% from 10 years ago. As highly active antiretroviral therapy (HAART) prolongs periods of survival, the older population with HIV is likely to expand as well as the long term complications associated with the normal process of aging.
I will review briefly what I thought were the highlights of this joint IDSA/ICAAC conference in what relates to the complications of HIV. I will use what has become the "classic" organization of discussions about this particular issue.
Body composition
The term lipodystrophy refers to the body shape changes that HIV positive patients may suffer after the initiation of antiretroviral therapy. The initiation of antiretroviral treatment with the "classic" regimens is associated with initial gains in limb and abdominal fat, followed by progressive limb fat loss, with relative preservation of the fat gained in the abdomen. Lipoatrophy is the most characteristic body shape change associated with HIV infection, and is the one with the most profound metabolic and psychological implications for the patients. Lipoatrophy has been associated mainly with the use of particular nucleoside analogs (zidovudine and stavudine), and lately, in the study ACTG 5142, with the use of efavirenz, although I think that was an artifact of the particular definition of lipoatrophy used in that study. New antiretroviral regimens seem to be less prone for the developments of these problems. Although the long-term follow up with the new antiretroviral regimens recently approved is still limited, I can say that severe cases of lipoatrophy have become less frequent in my clinic over the last couple of years, since we have been avoiding thymidin analogs.
During this meeting there were not many presentations that are going to change our understanding or the management of this complication of HIV and its treatment. Not surprisingly there were not significant differences in changes in body fat when comparing two different boosted protease inhibitor regimens (fosamprenavir with 100 mg or 200 mg of ritonavir in addition to abacavir and lamivudine). The initial limb and trunk fat improvements that characterize the initiation of any antiretroviral regimen were maintained similarly with both regimens. The good news is that there were not significant amounts of subcutaneous fat loss during the follow, which contrast favorably with what we used to see with the use of "older" nucleoside backbones (H-2302)1.
Lipids
There has been considerable concern about an increased cardiovascular risk among patients with HIV infection receiving antiretroviral therapy. Patients with HIV infection have significant risk factors tha may contribute to the development of cardiovascular disease. First HIV infection and its treatment affects endothelial function. Second both HIV and its treatment is associated with an increased or pro-atherogenic dyslipidemia, the most important risk factor for the development of cardiovascular disease in the general population. Third, patients with HIV infection have high prevalence of other cardiovascular risk factors like smoking and diabetes mellitus, and the metabolic syndrome and last, HIV infection is associated with a state of chronic immune activation that doesn't resolve completely even if the patient is fully suppressed.
The presentations in this meeting that dealt with CVD risk were mostly epidemiological and retrospective in nature. A small prospective study performed coronary CT angiographies to quantify non-calcified plaque volume and calcium scores on 22 HIV+ adults and 22 HIV negative matched controls. In general there were not significant differences between HIV + individuals and the uninfected population, although obviously the study is too small to make very definitive conclusions2 (H2311). The results of this study were not surprising, as several studies have demonstrated that traditional risk factors are much more significantly associated with CVD risk than any HIV treatment related factors. Among HIV+ patients, however, duration of antiretroviral therapy was more closely associated with plaque volume than traditional markers of cardiovascular risk. Another large epidemiological study, with more than 4000 patients, showed that HIV infected patients from Latin America have a high frequency of dyslipidemia and a relatively elevated cardiovascular risk3 (H2310).
Several lifestyle interventions can have a significant and profound impact in the cardiovascular risk HIV-infected individuals. Smoking is extremely frequent among HIV-positive individuals and might be associated not only with an increased cardiovascular risk, but also with other metabolic complications like decreased bone mineral density. Life style changes, like increased physical activity and diet, are associated with improved lipid profile in HIV-infected individuals, particularly lowering triglyceride levels. However, in spite of all these traditional life style changes suggestions, many HIV-positive individuals still develop dyslipidemia that require medical treatment. If that is the case establishing and reaching LDL goals becomes the objective of the therapeutic intervention. During this conference a retrospective study compared the activity of different statins for the treatment of hyperlipidemia associated with HIV infection. Pravastatin was the less effective but also the less toxic of the group, while atorvastatin and rosuvastatin were similarly potent. In general the clinical experience in patients with HIV is greater with atorvastatin, which is a good reason to use it preferentially, especially now that these medications have become generic(H2303)4. Another study in healthy volunteers showed that tenofovir alone is associated with modest decreases in triglycerides5 (H2307), which could explain, at least in part, the results that were observed in the Gilead 903 study years ago that compared D4T and tenofovir containing regimens and showed that D4T was associated with worse lipid profile.
Other important studies regarding hyperlipidemia associated with HIV infection were presented more as part of traditional antiretroviral studies than in the complications section of the meeting. In general new antiretrovirals have better toxicity profiles than older antiretrovirals (this should not be a surprise for anybody as that is one of the reasons that drive pharmaceutical companies to develop new compounds). In probably the most important antiretroviral trial presented during this conference, the STARTMRK study, an initial regimen of raltegravir in combination with tenofovir and emtricitabine was compared to the classic tripe combination tenovoir/emtricitabine and efavirenz. Both combinations were equally effective, but the use of efavirenz was associated with greater gains in total cholesterol, low-density cholesterol, and triglycerides (P < 0.001 for each comparison). The differences, although statistically significant are modest and probably not very clinically relevant, but this better lipid profile of integrase inhibitor containing regimens may be a consideration to take into account at the time of initiation of an antiretroviral regimen, particularly in the patient with a high cardiovascular risk6 (H896a).
Insulin resistance
HIV infected patients are exposed to the same factors that have lead to an epidemic of obesity and diabetes in this and other countries. In addition the treatment of HIV infection and its side effects also play a significant contribution to the development of insulin resistance and diabetes. Several studies have shown that patients with HIV infection are at an increased risk of diabetes mellitus than the general population, the question is how much of it is related to HIV infection and its treatment, and how much is due to traditional risk factors.
During this conference, a large epidemiological study was presented that suggests that traditional risk factors play a much more significant role in the development of diabetes in patients infected with HIV than HIV associated factors7. The study by Adell Butt using the massive VA cohort, evaluated more than 6500 individuals (approximately half of them HIV infected). Older age, male gender, minority race, and BMI were associated with an increased risk of diabetes, while increasing amount of alcohol use and a history of drug abuse or dependence were associated with a lower risk of DM (H2306) probably secondary to a lower BMI in these groups). HCV co infection was associated with a higher risk of DM in the HIV infected, but not in the HIV uninfected group. Overall, HIV was associated with a lower risk of diabetes after adjusting for traditional risk factors.
In the past the use of specific antiretroviral drugs, particularly some protease inhibitors (indinavir and maybe lopinavir) have been associated with an increased risk of developing insulin resistance, even after very brief exposure to these drugs. Last year we learned that exposure to stavudine (a NRTI) can induce insulin resistance in HIV negative individuals. During this conference a study showed that the use of tenofovir alone in HIV negative is not associated with changes in insulin sensitivity evaluated in a euglicemic hyperinsulnimec clamp 5 (H2307). The results were not surprising, as there was not a suspicion that this drug would decrease insulin sensitivity. However another question was settled in this study: the use of tenofovir was associated with modest decreases in some lipid fractions what would explain some of the differences that were observed years ago in Gilead study 903 (see above).
Bone disease associated with HIV infection
Patients with HIV infection have an incredibly high prevalence of osteopenia and osteoporosis. The reasons for it are still not completely clear, but both HIV and treatment related factors contribute to it. Tenofovir has been associated in some studies to this problem, but other antiretrovirals probably contribute too. A study from Mount Sinai in New York looked at vitamin D level and PTH levels in 51 men receiving antiretroviral therapy. The title suggest that it would be appropriate to supplement patients receiving tenofovir with vitamin D. However, the title was a misnomer, as individuals receiving tenofovir didn't have lower levels of vitamin D in the blood. The study was a little bit confusing and has a small size for study of these characteristics. I think the main take-home message is that the frequency of low vitamin D levels his very high among patients with HIV infection. In fact low vitamin D levels are extremely common among the general population too; to the point that what it is defined as a "normal" vitamin D level in the general population is probably a low level. Clinicians taking care of HIV positive patients should consider any level below 25 ng/ml as low. In this study, patients receiving tenofovir and emtricitabine were also more likely to have slightly elevated PTH levels, something that is frequent among patients with low vitamin D level s (an attempt by the body to restore normocalcemia).
Other interesting results regarding HIV and bone disease came from the SMART study (H-2312a )9. The SMART study has given a lot of insight about the role of HIV infection itself in driving many of the "non AIDS defining events" that individuals with HIV infection suffer at any CD4 cell count level. In this study individuals were randomized to two different strategies: chronic viral suppression or CD4 driven antiretroviral therapy. In this small sub-study of approximately 400 individuals, those individuals randomized to start and stop therapy based on their CD4 cell count had increases of bone mineral density immediately after discontinuing antiretroviral therapy. These findings are exactly the reverse of what is seen in individuals starting antiretroviral therapy: after the initiation of antiretroviral therapy patients on average lose approximately 2-3% of their bone mass. In the SMART study, the discontinuation of antiretrovial therapy was associated with a transient improvement in BMD, and subsequent decreases similar to the ones seen in the patients receiving antiretroviral therapy chronically. These findings, together with what we know about the effects of starting antiretroviral therapy, suggest that the immunologic and inflammatory changes associated with the initiation and the immediate discontinuation of antiretroviral therapy have opposite effects on bone. The immediate clinical relevance of these small changes is questionable, but in the long run they might become relevant as both osteopenia and osteoporosis are extremely frequent in patients with HIV infection and this population ages. It is important to point out that in spite of the apparent paradoxical "improvement" of BMD after treatment interruption, this" benefit" does not outweigh the known and significant risks of treatment interruptions in patients living with HIV.
Other Complications
Renal disease
Although large prospective studies suggest that the use of tenofovir, specially with relatively close clinical follow up is safe, observational studies suggest that tenofovir is associated with renal toxicity, principally in patients with an underlying systemic or renal disease. Richard Moore and Joe Gallant looked at the John Hopkins cohort 10and found that modest decreases in creatinine clearance are observed both in patients that start a tenofovir including regimen, but also in patients that start other nucleoside analog containing regimen. Although the risk of significant renal toxicity is generally small, their study suggest that older patients, on protease inhibitor containing regimens, those with CD4 counts< 200 cells/mm3, and those with hypertension are the most prone to develop this complication and should be monitored more closely (H2297).
Bacterial infections
The WHO guidelines for the care of patients living with HIV in resource limited settings, a document recently updated (July 2008) recommends the use of co-trimoxazole prophylaxis in all patients with HIV infection and CD4 cells counts below 350 cells/mm3. The WHO also suggest that if CD4s are not readily available (basically all the developing world) all patients with HIV infection should receive TMP-SMZ. The reason for this is the result of two randomized trials that have shown a decrease of mortality and hospital admissions in patients receiving this type of prophylaxis, as well as a decrease in the incidence of malaria in areas of the world with an elevated prevalence.
In this conference data was presented suggesting that this intervention carries a significant price. Data from Zambia (Poster H2324) and Botswana (oral presentation C2-221) showed an alarming increase in the incidence of Staphylococcus aureus resistance to sulfas in Africa. The rate of resistance of Staphylococcus aureus is greater than 80% in those countries. This is especially significant when it is compared to the resistance rates in United States where co-trimoxazole resistance is relatively low (less than 10-20%). The high frequency of community associated MRSA infection in our country has made TMP-SMZ the treatment of choice for the management of MRSA infections. We know that MRSA skin infections are particularly common among HIV infected individuals in this country. If the problem of skin MRSA infections starts extending in Africa, something not unexpected in this era of disease globalization, it may become a problem very difficult to control because the lack of accessibility to much more expensive alternative antibiotics like linezolid.
References
1. H-2302. Limb and Trunk Fat Changes by Total Body DEXA After 96 Weeks of Treatment with Once-Daily (QD) Fosamprenavir (FPV) Boosted with either 100 mg or 200 mg of Ritonavir (/r) plus Abacavir (ABC)/Lamivudine(3TC): COL100758. D. WOHL, E. DEJESUS , L. SLOAN , M. SENSION , Q. LIAO , K. PAPPA , K. OIE , C. HICKS . 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
2. H-2311. Coronary Plaque Volume by CT Angiography Correlates with Duration of Antiretroviral Therapy
C. HADIGAN1, L. HEALEY 2, N. MULDOON 2, J. SANKO , P. GEORGOFF , A. M. GHARIB. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
3. H-2310. Metabolic Profile and Cardiovascular Risk Factors in Latin American HIV Patients Receiving HAART. P. CAHN , O. LEITE , A. ROSALES , R. CABELLO , C. ALAVAREZ, L. DEIBIS , C. ZALA , T. SUFFERT , Rapid Ii Study Group. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
4. H-2303. Effectiveness of Individual HMG CoA Reductase Inhibitors (Statins) in HIV-Infected Patients in Clinical Care. S. SINGH 1, H. M. CRANE, J. WILLIG , M. J. MUGAVERO , M. SAAG , R. D. HARRINGTON , M. M. KITAHATA. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
5. H-2307. The Impact of Tenofovir on Insulin Sensitivity and Lipids in Healthy Volunteers
P. RANDELL1, A. JACKSON , L. ZHONG , K. YALE , G. MOYLE. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
6. STARTMRK, A Phase III Study of the Safety & Efficacy of Raltegravir (RAL)-Based vs Efavirenz (EFV)-Based Combination Therapy in Treatment-Naïve HIV-Infected Patients-- J. LENNOX1, E. DEJESUS 2, A. LAZZARIN 3, R. POLLARD 4, J. MADRUGA 5, J. ZHAO 6, X. XU 6, A. WILLIAMS-DIAZ 6, A. RODGERS 6, M. DINUBILE 6, B. NGUYEN 6, R. LEAVITT 6, P. SKLAR 6;. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
7. H-2306. HIV Infection and the Risk of Diabetes Mellitus. A. BUTT1, K. MCGINNIS , M. RODRIGUEZ-BARRADAS , S. CRYSTAL , M. SIMBERKOFF , M. GOETZ , D. LEAF , A. JUSTICE. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
8. H-2300. Should Vitamin D Be Prescribed with Tenofovir/FTC?-- K. CHILDS, S. FISHMAN, K. BATEMAN, S. FACTOR, C. WYATT, M. MULLEN, A. BRANCH. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008.
9. H-2312a Continuous Antiretroviral Therapy (ART) Decreases Bone Mineral Density: Results from the SMART Study-- B. GRUND1, A. CARR 2, The Insight Smart Study Group. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008.
10. H-2297. Renal Function after Use of Tenofovir as Part of the Initial ART Regimen
R. MOORE, J. GALLANT. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
11. H-2324.High Antibiotic Resistance of Staphylococcus aureus in HIV Infected Persons in Rural Africa-- F. P. N. MOLLEMA1, J. H. VAN DIJK 2, H. A. VERBRUGH 1, A. VAN BELKUM 1, J. L. NOUWEN. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008.
12. C2-221.Epidemiology of Methicillin-Resistant Staphylococcus aureus Bacteremia in Botswana-- M. BAFANA1, S. M. WOOD 2, A. J. RATNER 3, P. A. MEANEY 2, S. S. SHAH 2, A. P. STEENHOFF 2. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008.
13. H-2319. Pascual J, Pareja, A. Caminoa A, et al. HAART is associated with a lower level of hepatic necroinflamatory activity in HIV-HCV coinfected patients with CD4 > 350 at the time of liver biopsy. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC.
14. H-896b.Kitahata MM, Gange SJ, Moore RD. Initiating rather than deferring HAART at a CD4 count between 351-500 cells/mm3 is associated with improved survival. Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC.
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