HIV Treatment Guidelines

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Chapter: Essential pharmacology : Antiviral Drugs

The treatment of HIV infection and its complications is complex, prolonged, needs expertise, strong motivation and commitment of the patient, resources and is expensive.


HIV TREATMENT GUIDELINES

 

The treatment of HIV infection and its complications is complex, prolonged, needs expertise, strong motivation and commitment of the patient, resources and is expensive. Antiretroviral therapy is only 20 years old, and strategies are still evolving. Initially, anti-HIV drugs were used singly one after the other as each failed in a patient due to emergence of resistance. Understanding the biology of HIV infection and availability of several potent drugs belonging to different classes has mandated ‘highly active anti-retroviral therapy’ (HAART) with combination of 3 or more drugs whenever indicated. Mono-therapy is contraindicated.

 

It has been realized that even with HAART, which rapidly kills > 99% virions, a small number survive within the resting CD4 lymphocytes and invariably give rise to relapse when treatment is discontinued despite complete absence of detectable viraemia and normal CD4 cell count for years. Moreover, HIV reverse transcriptase is highly copying error prone, implying that viral replication produces changes at some base pairs (and codons) with high frequency—rate of mutation is high. Some mutations confer resistance to one or the other antiretroviral drugs. The resistant mutants are selected by anti-HIV therapy and in time an apparently sensitive population is replaced by resistant virions. As the disease progresses in the individual (and several anti-HIV drugs are used) the HIV population becomes genetically complex and diverse with respect to susceptibility to drugs. Each failing regimen limits future treatment options. Even primary drug resistance (i.e. in untreated patients) is being detected in ~10% HIV patients.

 

Since none of the currently available regimens can eradicate HIV from the body of the patient, the goal of therapy is to maximally and durably inhibit viral replication so that the patient can attain and maintain effective immune response towards potential microbial pathogens. Greater the suppression of viral replication, lesser is the chance of emergence of drug resistant virus.

 

Initiating Antiretroviral Therapy

 

Although it is attractive to treat all symptomatic and asymptomatic HIV positive patients, no long-term clinical benefit has been demonstrated in asymptomatic cases with reasonable immune competence (CD4 cell count > 350/μl). Arguments against early treatment in asymptomatic stable patients include—deleterious effect of antiHIV drugs on quality of life, their side effects and toxicity, especially lipid abnormalities, drug interactions, risk of drug resistance limiting future treatment options, limited durability of available regimens, risk of dissemination of resistant virus and high cost. The best time to initiate antiHIV therapy remains uncertain. Various professional bodies and health authorities have framed treatment guidelines from timetotime. A summary of current concensus is presented below.

 

1. CD4 cell count is the major determinant of initiating therapy in asymptomatic cases. Increased mortality occurs when treatment is begun after CD4 count has fallen below 200/μl, because the patient is at high risk of serious opportunistic infection, and response to antiHIV drugs is suboptimal.

2. All cases of symptomatic HIV disease—treatment recommended.

3. Asymptomatic HIV disease with CD4 count < 200/μl —treatment recommended.

4. Asymptomatic HIV disease with CD4 count > 200/μl —treatment decision to be individualized based on:

 

·          CD4 cell count and rate of decline: Most authorities agree that patients with > 350 CD4 cells/μl need not be treated. Thus, treatment may be initiated at CD4 count between 200–350/μl depending on other considerations. A decline of > 100 CD4 cells/μl per annum is considered high—and an indication for initiating therapy.

·          HIVRNA level: > 50,000 copies of HIVRNA/ml is considered high. However, many authorities recommend treatment in patients even with > 20,000 copies/ ml.

·          Patient’s interest and potential to adhere to therapy.

·          Individual risks of drug toxicity and interactions.

 

Therapeutic Regimens

 

Whenever treatment is instituted, it should be aggressive (HAART) aiming at suppressing plasma viral load to undetectable levels (< 50 copies of HIVRNA/ml). Therapy with 3 antiretroviral drugs is considered optimal. Addition of a 4th drug to treatment-naïve patients affords no additional benefit; may be tried in failed patients. Due to availability of multiple drugs, a variety of combination regimens are possible and have been employed. However, no specific combination can be considered optimal initial regimen for all patients. Choice has to be made on the basis of efficacy, durability, tolerability, convenience, drug interactions, impact on future options and cost.

 


 

Some of the preferred and alternative regimens for initial treatment (employing ARV drugs currently available in India) are given in the box. The important general points are:

 

·          The 3 drugs in the regimen should belong to at least 2 different classes. Single class regimens are inferior. There is convincing evidence that 3NRTI regimens are clinically less effective than those which include a NNRTI or a PI.

 

·             The 3 NRTI regimen is employed only when a NNRTI or PI cannot be used; such as in patients receiving rifampin or other interacting drugs.


·     The PI sparing regimens (2 NRTI + NNRTI) are more convenient with lower pill burden, simpler dosing schedules, more acceptable, better tolerated and produce less metabolic complications; are preferred by many.

 

·          The 3 class regimen (NRTI + NNRTI + PI) is reserved for advanced cases who have failed multiple earlier regimens, so as to avoid multiclass resistance and higher toxicity.

 

·          If drug toxicity develops, either the entire regimen should be interrupted or the offending drug should be changed. No dose reduction should be tried.

 

·          ‘Drug holidays’ or ‘structured treatment interruptions’ may briefly improve well being (by absence of side effects), but allow viral replication and increase risk of drug resistance; are not recommended.

 

·          Treatment is practically lifelong.

 

·          Pregnancy in women does not contraindicate antiHIV therapy. Drugs considered relatively safe during pregnancy are: Zidovudine, lamivudine, nevirapine, nelfinavir, saquinavir.

 

·          The ARV drug combinations that should not be employed are given in the box.

 


Antiretroviral drug combinations to be avoided

When indicated, PEP should be started as soon as possible, preferably within 1–2 hours of exposure. The likelihood of preventing infection declines with the delay; some guidelines do not recommend starting it beyond 72 hours of exposure. According to others, in case of default, PEP may even be started even 1–2 weeks later. Though HIV infection may not be prevented, onset of AIDS may be delayed by the late-start PEP.

 

Prophylaxis Of HIV Infection

 

Perinatal prophylaxis HIV may be transmitted from the mother to the child either through the placenta, or during delivery, or by breastfeeding. The highest risk of transmission is during the birth process. In HIV positive women who are not receiving ART, zidovudine (300 mg BD) started during 2nd trimester and continued through delivery to postnatal period, with treatment of the neonate for 6 weeks has been found in clinical trials to reduce the chances of mother to child transmission by 2/3rd. Combination therapy is even more effective. Even if not started earlier, zidovudine administered during labour and then to the infant is also substantially protective. Many obstetricians offer 3 drug ART to HIV positive asymptomatic women after the 1st trimester. Breastfeeding by HIV positive mother should be discouraged, as it may transmit the virus to the infant.

 

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