|Year : 2005 | Volume
| Issue : 3 | Page : 113-118
|Advances in management of HIV infection
From the department of Internal Medicine, Calcutta Medical Research Institute, India
, AISHANI, DA 5, Salt Lake I, Kolkata-700 064.
Source of Support: None, Conflict of Interest: None
Keywords: HIV infection, Management, Advances
|How to cite this article:|
Mukherjee S. Advances in management of HIV infection. Indian J Dermatol 2005;50:113-8
The HIV epidemic began more than two decades ago. According to WHO and UNAIDS more than 40 millions were infected till 2001 and approximately 25 million had died. India shares 10% of global HIV burden and 65% of South-East Asian population. It is reported that 5.1 million HIV infection exist in India with prevalence rate of 0.96% upto 2003. Globally about 16,000 new infection with HIV occur daily. Over 90% of the infected persons live in the developing world with inadequate scope for current treatment.
The course of the HIV disease spans over a period of 15-20 years. The HIV infected patients needs holistic care continuously from the time of diagnosis till the end. The basic ingredients of treatment are counselling, psychosocial and nutritional support throughout the period apart from antiretroviral therapy. The role of nutritional support, use of antioxidants, glutathiones and B12 to improve 'T' cell function and impaired survival have been reported in asymptomatic patients with preserved CD4 counts.
The turn of century has changed the attitude of use of antiretroviral therapy in HIV infected subjects following World AIDS Conference in Durham in 2000 both for the developed and developing countries. The UN GASS Declaration in 2001 urged that HIV care and HIV prevention should be complementary, and committed government to providing the highest attainable standard of care, including ARV treatment for people living with HIV/AIDS. Following the use of ARV therapy there is plateauing effect or even downward trend in mortality in USA in contrast to India wherein the access to modern therapy is meant for the few rich people and mortality is still high. However there is a 'paradigm shift' in HIV care from general care and treatment of opportunistic infection to access to ARV therapy to slow down HIV progression and transmission even in India. Thus HIV infection once considered a fatal disease of 1980s has become a manageable disease today.
The changing dimensions of HIV therapy have evolved over a period of time following better understanding of HIV replication inside the host's lymphocytes (CD after the entry till the release of virions and subsequent destabilization of immune system of the host.
Goals of therapy : The goals of therapy are
Primary : To attain maximal and durable viral suppression.
To reconstitute or preserve immune system.
Secondary : To reduce HIV related morbidity and mortality.
To improve quality of life.
While fulfilling these goals it is prudent that optimal therapy should also prevent the emergence of drug resistance and ultimately prevent treatment failure for a significant amount of time. Early aggressive induction followed by maintenance therapy is the keyword to success.
Based on this concept Highly Active Antiretroviral Therapy (HAART) has been accepted as the modality of treatment. The term HAART indicates use of two NRTIs along with an NNRTI or a boosted PI, so as to achieve goals elucidated before.
| When to start ARV therapy?|| |
WHO recommends that, in resource-constrained settings, persons with symptomatic disease (AIDS, WHO adult stage IV and advanced stage III disease) should receive ARV treatment irrespective of the CD4 count or total lymphocyte count. Therapy is also recommended for symptomatic disease (WHO adult stage II & III) and asymptomatic (WHO adult stage I) disease when CD4 count nears and falls below 200/mm3 or when CD4 percentage is below 15%. When CD4 cell count is not available, treatment is recommended for symptomatic patients (WHO adult stage II and III) with TLCs below 1200/mm3.- However, when only TLCs are available, asymptomatic persons needing therapy cannot be accurately identified and only become eligible for treatment when their HIV disease progresses and symptoms are apparent as shown in [Table - 1].
Before selecting proper drug regimen for control of HIV infection it is important to consider both viral factors and patient factors.
The viral factors are as follows:
1. Very high rate of replication of virus i.e. about 10 billion viral particles are produced daily.
2. Very high mutation rate: each cycle viral replication produces are mutation per genome i.e. 104 to 105 mutations at each site daily.
3. Very high plasticity : The proteins targeted by ARV can still function on despite the presence of many mutations.
The patient factors include poor adherence, compliance, drug toxicity, pill burden, drug interactions and cost of therapy which pose to limit the successful outcome.
Considering all these issues proper drug selection in combination (sequencing) is mandatory all through natural history of the disease.
In the recommended regimens each containing a dual nucleoside component as backbone therapy is to be combined with either a protease inhibitor (PI) and NNRTI or the potent NsRTI - abacavir (ABC). In this context the potential dual NsRTI components have to be considered as below:
(b) d4T + 3TC
(c) d4T + ddl
(d) ZDV + ddl
(f) ddl +3TC
Although direct comparative data are limited these five dual nucleoside components appear to possess comparable inherent antiviral activity in treatment-naive persons. On the grounds of efficacy, toxicity, clinical experience and fixed dose combination availability ZDV and 3TC is prescribed as the initial dual NsTRI component of choice. The combination of ZDV and d4T should never be used because of antiviral antagonism.
In order to establish a potent ARV regimen a third drug must be added to the dual nucleoside backbone to stop the emergence of drug resistance., The three combinations to consider involve addition of one of the following :
(c) a booster PI (for pharmacoenhancement with low dose ritonavir). Following [Table - 3] shows the standard triple combination for regular use.
The long term success of ARV therapy is dependent on low baseline viremia, higher basal CD4 count, potency of ARVs, adherence to therapy and initial rapid therapeutic response.
NNRTI are very potent Anti-HIV-1 agents in genernal but are inactive against group O HIV-1 subtype and HIV-2. For group O HIV-1 subtype or HIV-2 infections only the triple NsRTI and PI-based regimens should be used because of inherent resistance of these virus to the NNRTI class of compounds.
| When to change therapy?|| |
Alteration of initial ARV is done in cases of poor drug tolerance, drug toxicity, presence of TB or pregnancy and treatment failure. e.g., d4T substituted for ZDV related anemia, NVP for EFZ in case of pregnancy.
WHO recommends that patients experiencing treatment failure should switch from first line to a completely different second line combination regimen as in following [Table - 4].,
Monitoring of response
The regular monitoring of ARV is important for assessing the effectiveness of the intervention and ensuring adherence and safety. The components of monitoring are :
1. Clinical monitoring - to check for adherence, clinical benefits, drug specific toxicity and interactions. It is important to record body weight, fever, diarrhoea. rash, HIV related disease progression and signs of immune reconstitution syndrome.
2. Laboratory monitoring - consists of CD4 count, plasma HIV-RNA at baseline and then at 6 weeks. Then CD4 count is recommended after 12 and 24 weeks. The immunological failure is characterized by fall of at least 30% from the peak value following therapy or return to pre-therapy baseline. On the other hand increase of over 100 CD4 cells/mm3 in the first 6-12 months in an ARV-naive, adherent patient with drug-susceptible virus. HIV- 1 RNA is clearly a useful indicator of the activity of ARV requirement in individual patient but it cannot be measured frequently in resource-restricted country. In future, viral load testing and viral resistance assays where available, would probably be limited to the central level of the health system.
3. Organ functions - liver, CVS, kidney, CNS are to be monitored in individual cases.
Therapeutic drug monitoring (TDM) is a novel approach for future in special situations like in presence of drug interactions, drug toxicity. virological failure and pregnancy by which therapy become more definitive.
| Comorbidities|| |
Tuberculosis is a leading cause of death among HIV-infected patients. WHO estimated that TB accounted for 30% of AIDS related death in 1999. The management of HIV and TB co-infection is complicated because some antiretroviral agents produce unacceptable drug interactions with ATD and can magnify the toxicity of TB treatment. Immediate ATD initiation and DOT is the priority at very high risk for HIV disease progression and mortality e.g, a CD4 count below 200 cells/mm3 or extrapulmonary TB.- The recommendation of ARV and ATD is guided mostly in individuals by CD4 count -[Table - 5].
The use of other PIs (NFV, IDV/r, LPV/r) is contraindicated because rifampicin induces hepatic enzymes to achieve subtherapeutic levels of PIs.
In TB, immune reconstitution syndrome following initiation of ARV within 2-3 weeks of administration has been reported in about 30% cases. However ARV should not be interrupted in such circumstances.
Preventive therapy for TB may not be feasible in many resource limited settings because of difficulty in excluding active disease. The INH prophylaxis is only indicated for 6 months for reactors to the tuberculin skin test and negative chest X-ray.
In HIV and hepatitis co-infection there is always disease potentiation with activity and higher rate of ARV hepatotoxicity., Because of possibility of additive toxicity regimens with ddl/d4T and/or NVP should be avoided in patients with active hepatitis. The prioritization of treatment has to be determined and standard treatment of hepatitis need to be initiated. The dual action drugs for B-hepatitis are 3TC, TDF and emtricetabine., Interferon alfa and ribavarin are continued in HCV infection as per recommendation. Monitoring of liver function at regular intervals is necessary.
There are three crucial steps for entry of HIV into the CD4 T cells namely
1. binding of HIV to the CD4 receptors - 'attachment' inhibitors.
2. binding to co-receptors - coreceptor antagonists.
3. fusion of virus and cell - fusion inhibitors
These are called as a group entry inhibitors and number of drugs are on the pipeline in this group out of which T-20 or enfuvitide binds to HIV gp 41 - protein during fusion of HIV with the target cell and commonly recommended for salvage therapy., Survival benefit has been shown in TORO study when given by subcutaneus injection daily. The pagylation of T-20 is under study for weekly dosing.
Other drugs in this group include Pro 542, SCH-D1 T-649 etc. Among combination products two new combination drugs create new options with reduced pill burden of once or twice a day. These are made up of 600 mg ABC and 300 mg 3TC, 300mg TFV and 200 mg FTC; they are approved by FDA in August 2004.
Other 'newer' drugs under different classes are increasingly studied for the future. These are tabled below. [Table - 6]
The drugs are still experimental and final results of phase Ill studies and official approval are awaited. Attempts have been made to reduce toxicity and pill burden, and to enhance adherence for survival advantages.
| Immunotherapy in clinical practice|| |
In recent years, in addition to 'conventional' ARV, immunomodulatory treatment strategies have been investigated to an increasing extent. Limited success have been observed in some selected patients with the use of some 'new' drugs which are addressed as below.
Interleukin-2 - It is a cytokine from activated T cells and induces proliferation and cytokine production in T cells, B cells and NK cells. It is now given subcutaneously over 5 days, in cycles 6-8 weeks apart.- The viral load is usually unaffected by IL-2. Two important trials ESPRIT and SILCATT have shown some encouraging results to reconstitute immune system in patients whose CD4 count remain below 100 m despite good viral suppression.
Other drugs like hydroxyurea, interferon, cyclosporin A, mycophenol have been tried in several small studies to slow down viral replication but ultimately are proved to be abortive. Therapeutic vaccination has not been successful so far in HIV therapy
| References|| |
|1.||UNAIDS AIDS Epidemic Update 2004 http/inv.net.link.php?id=227 |
|2.||Sepkowitz KA. AIDS - the first 20 year. N Engl J Med 2001; 344 :1764-72. |
|3.||Fanci AS. The AIDS epidemic - consideration for the 21st Century. N Engl J Med. 1999; 341 :1046-50. |
|4.||Carpentev CC, Caper DA. Fisohi MA, et al. Antiretroviral therapy in adults:updated recommendations of the International AIDS Society - USA Panl. JAMA 2000; 283 : 381-90. |
|5.||Cozzi Lepsi A, Philips AN, d'Arimino Monforte A, et al. When to start HAART in chronically HIV-Infected patients : evidence from the ICONA study. AIDS 2001; 15 : 983-90. |
|6.||Fournier AM, Sosenko JM. The relationship of total lymphocyte count to CDH lymptocyte cents in patients infected with HIV. Am J Med Science 1992; 304:79-82. |
|7.||BHIVA. British HIV Association (BHIVA) guidelines for the treatment of HIV infected adults with antiretroviral therapy. HIV Med 2001; 2 : 276-313. |
|8.||Holinberg SP, Hambuger ME, Moorman AC, Wood KC, et al. Factors associated with maintainance of long term plans in HIV virus RNA suppression. Clin lnf Disease 2003; 37:702-5. |
|9.||Grabor S, Kongsingnian I, Sobel A, et al . Immunologic and clinical responses to HAART thrapy over 50 yrs. of age. AIDS 2004; 18 : 2029-38. |
|10.||Hogg RS, Yip B, Kully C, et al . Improved survival among HIV-infected patients after initiation of triple drug antiretroviral regimens. Cmaj 1999; 160 : 659-65. |
|11.||Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral naive HIV-1 infected adults. AIDS 2001; 15:1369-77. |
|12.||Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356:1423-30. |
|13.||Hogg RS, Yep B, Chau KJ. Rates of disease progression by baseline CD4 count and viral local adlen initiating triple drug therapy. JAMA 2001;286; 2568-77. |
|14.||Dreohster H, Powderly WG. Effective antiretroviral therapy: a review. Clin Inf Disease 2002;35;1219-30. |
|15.||Mocroft A, Philips AN, Miller V, et al. The use and response to second line protease inhibitor regimens; results from EUROSIDA study. AIDS 2001; 15;201-9. |
|16.||Ghani AC, dwolf F, Ferguson NM, et al. Surrogate markers for disease progression in healed HIV infection. J Acquir Immune Defficiency Syndrom 2001; 28 : 226-31. |
|17.||Telentic A. New developments in laboratory monitoring of HIV infection. Clin Micro Bio Infecto 2002; 8; 137-43. |
|18.||Mellors JN, Munoz AM, Giorgi JV, et al. Plasma viral load and CD4 lymphocytosis as per prognostic markers of HIV-I infection. Ann Int Med 1997; 126 : 946-54. |
|19.||Back D, Gatti G, Fletehev G, et al. Therapeutic drug monitoring in HIV infection. AIDS 2002;Suppl 1:55-37. |
|20.||Badri M, Ehrlich R, Wood R, et al. Association between TB and HIV disease progression in a high tuberculosis prevalances area. Int J Tubero Lung Disease 2001; 5 : 225-32. |
|21.||Dean GL, Edwards SG, Ivas NJ, et al. Treatment of TB in HIV-infected persons in the era of HAART. AIDS 2002; 16: 75-83. |
|22.||Hing CC, Chen MY, Hsiao CF, et al. Improved outcomes of HIV-l infected adults with TB in the era of HAART. AIDS 2003; 17 ; 2615-22. |
|23.||Soriano V, Puoti M, Sulkowski M, et al. Care of patients with Hepatitis C and HIV coinfection. AIDS 2004;18 :1-12. |
|24.||Braun N. Update on chronic hepatitis C in HIV/HCV-coinfected patients : viral interactions and therapy. AIDS. 2003 Nov 7; 17 : 2279-90. |
|25.||Brook MG, Gilson R, Wilkins EL. BHIVA Guidelines : coinfection with HIV and chronic hepatitis B virus. HIV Medicine 2003;4:42-51. |
|26.||Rockstroh JK. Management of hepatitis B and C in HIV co-infected patients. J AIDS 2003; 34 Suppl 1: S59-65. |
|27.||Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp4l-mediated virus entry. Nat Med 1998 ;4:1302-7. |
|28.||Arasteh K, Lazzarin A, Clotet B, et al. TORO : 96 week virological and immunological response and safety evaluation of enfuvirtide with an optimized background. Abstract, XV Int AIDS Conf, Bangkok; 2004 . |
|29.||Hornberger J, Green J. Clinical prognosis of enfuvirtide in combination with an optimized background regimen among categories of baseline CD4+ cell count and HIV antiretroviral resistance. Abstract 478, 2nd lAS 2003, Paris. |
|30.||Lalezari JP, Henry K, OHearn M, et al . Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003;348: 2175-85. |
|31.||Gewurz BE, Jacobs M, Proper JA, Dahl TA, Fujiwara T, Dezube BJ. Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1 : a phase 1 study. J Infect Dis 2004;190:1957-61. |
|32.||Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease inhibitor resistant HIV-1 clinical samples. AIDS 2000;14 :1943-8. |
|33.||Stellbrink HJ, van Lunzen J, Westby M, et al. Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial). AIDS 2002;16 :1479-87. |
|34.||Abrams Dl, Bebchuk JD, Denning ET, et al. Randomized, open-label study on the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of >or=300/mm3: CPCRA 059. J AIDS 2002; 29: 221-31. |
|35.||Chun TW, Engel D, Mizell SB, et al . Effect of interleukin-2 on the pool of latently infected, resting CD4+ T Cells in HIV-1 -infected patients receiving HAART. Nat Med 1999; 5 : 651-5. |
|36.||Havlir DA, Gilbert PB, Bennett K, et al . Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression. AIDS 2001; 15 :1379-88. |
|37.||Haas DW, Lavelle J, Nadler JP, et al . A randomized trial of interferon alpha therapy of HIV type 1 infection. AIDS Res Hum Retrovir 2000; 16 :183-90. |
|38.||Sankatsing SU, Jurriaans S, van Swieten P, et al . Highly active antiretroviral therapy with or without mycophenolate mofetil in treatment-naive HIV-1 patients. AIDS 2004; 18 :1925-31. |
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]
| Article Access Statistics|
| Viewed||7159 |
| Printed||217 |
| Emailed||1 |
| PDF Downloaded||7 |
| Comments ||[Add] |